{"gene":"KCNE1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1996,"finding":"KCNE1 (minK/IsK) coassembles with KCNQ1 (KvLQT1) to form the cardiac slow delayed-rectifier potassium channel (I(Ks)). Coexpression of the two subunits in heterologous systems produced a current nearly identical to native cardiac I(Ks), establishing KCNE1 as an obligate beta-subunit of this channel complex.","method":"Heterologous coexpression in Xenopus oocytes; electrophysiology","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution of native current by coexpression, foundational result independently replicated across many subsequent labs","pmids":["8900283"],"is_preprint":false},{"year":1996,"finding":"KCNE1 (IsK) knockout mice lack potassium secretion into endolymph by strial marginal cells and vestibular dark cells, demonstrating that IsK is required for transepithelial K+ secretion in the inner ear.","method":"IsK gene knockout mouse; in vitro short-circuit current measurement of inner ear epithelia","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with specific epithelial transport phenotype, replicated in subsequent knockout studies","pmids":["8982171"],"is_preprint":false},{"year":1991,"finding":"The 63-amino-acid sequence covering the transmembrane domain of ISK is sufficient for K+ channel activity. The cytoplasmic region immediately C-terminal to the transmembrane domain is critical for channel activity, while amino-terminal substitutions had little effect. Specific transmembrane residues (e.g., L52I) alter gating properties, supporting ISK as an integral part of the channel pore.","method":"Site-directed mutagenesis, deletion/truncation analysis, Xenopus oocyte expression, electrophysiology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with electrophysiological readout, multiple constructs tested in single rigorous study","pmids":["1939241"],"is_preprint":false},{"year":1993,"finding":"IsK protein expression in Xenopus oocytes induces not only a slow K+ current but also a Cl-selective current. Mutagenesis identified distinct N-terminal and C-terminal domains as critical for Cl- and K+ channel activities respectively, supporting a model in which IsK acts as a regulatory activator of distinct endogenous channel complexes.","method":"Site-directed mutagenesis; Xenopus oocyte electrophysiology","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — mutagenesis with functional readout in single study; Cl- channel identity not fully resolved in this paper","pmids":["8413671"],"is_preprint":false},{"year":2008,"finding":"The three-dimensional NMR structure of KCNE1 shows a curved alpha-helical transmembrane domain flanked by extracellular and intracellular helices. Experimentally restrained docking suggests KCNE1 slows KCNQ1 activation by interacting with the S4-S5 linker in the closed state and binds a gain-of-function cleft in the open state to increase conductance and stabilize the open state.","method":"Solution NMR structure determination; computational docking to KCNQ1 models; functional validation","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with experimentally restrained docking and functional correlation; confirmed in lipid bilayer environment by subsequent EPR studies","pmids":["18611041"],"is_preprint":false},{"year":2010,"finding":"The stoichiometry of the KCNQ1-KCNE1 complex is flexible, with up to four KCNE1 subunits associating with the four KCNQ1 subunits (up to 4:4). Both voltage-dependence and gating kinetics depend on the relative expression densities of KCNQ1 and KCNE1, suggesting heart rhythm can be regulated by KCNE1 expression level and resulting stoichiometry.","method":"Single-molecule fluorescence subunit counting (bleaching); electrophysiology at varied KCNQ1:KCNE1 expression ratios","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — single-molecule counting is a rigorous quantitative method; functional correlate measured simultaneously; confirmed by subsequent studies","pmids":["20962273"],"is_preprint":false},{"year":1999,"finding":"Four LQT5 KCNE1 mutants show distinct cellular phenotypes: V47F and W87R traffic to the cell surface with altered IKs gating; L51H is retained intracellularly and fails to interact functionally with KvLQT1 or HERG; D76N suppresses both IKs and IKr. This establishes KCNE1 as a co-factor for both IKs and IKr channel function.","method":"Electrophysiology in Xenopus oocytes and HEK293 cells; immunocytochemistry for surface expression","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple complementary methods (electrophysiology + immunocytochemistry), multiple mutants with distinct phenotypes in two expression systems","pmids":["10400998"],"is_preprint":false},{"year":2007,"finding":"KCNQ1/KCNE1 channel complex undergoes RAB5-dependent endocytosis and RAB11-dependent exocytosis/recycling to the plasma membrane. Serum- and glucocorticoid-inducible kinase 1 (SGK1) enhances exocytosis via phosphorylation of phosphoinositide 3-phosphate 5-kinase and generation of PI(3,5)P2, providing a mechanism for stress-induced acceleration of cardiac repolarization.","method":"Dominant-negative Rab GTPase constructs; pharmacological inhibition; biochemical trafficking assays; electrophysiology","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (dominant-negative GTPases, kinase pathway dissection, functional readout) in single study","pmids":["17293474"],"is_preprint":false},{"year":2005,"finding":"PIP2 directly regulates the KCNQ1-KCNE1 complex; three LQT-associated KCNQ1 mutations (R243H, R539W, R555C) reduce PIP2 affinity of the channel, and direct PIP2 application or restoration of positive charge rescues channel activity, establishing impaired PIP2 interaction as a molecular mechanism for these LQT mutations.","method":"Giant excised patch electrophysiology; direct PIP2 application; MTSET chemical rescue; soluble PIP2 analog binding assay","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal biochemical and electrophysiological methods in single study, including chemical rescue confirming mechanistic model","pmids":["15746441"],"is_preprint":false},{"year":2001,"finding":"cAMP regulation of the KvLQT1/IsK (IKs) complex requires anchoring of protein kinase A (PKA) to the channel complex via A-kinase anchoring proteins (AKAPs). Coexpression of AKAP79, mAKAP fragment, or AKAP15/18 restored cAMP-dependent upregulation of IKs in heterologous cells; Ht31 peptide (disruptor of PKA anchoring) prevented the effect.","method":"Whole-cell patch clamp in mammalian heterologous expression systems; AKAP coexpression; Ht31 peptide disruption","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — functional epistasis with AKAP coexpression and dominant-negative disruption; multiple AKAP constructs tested","pmids":["11299204"],"is_preprint":false},{"year":2006,"finding":"KCNE1 requires co-assembly with specific K+ channel alpha-subunits for efficient trafficking and cell surface expression; without co-assembly, KCNE1 is retained in the early secretory pathway. Co-assembly mediates progression through the secretory pathway.","method":"Enzymatic deglycosylation; immunofluorescence; quantitative cell-surface labeling in multiple cell lines","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in multiple cell lines; mechanistic trafficking conclusion supported by complementary approaches","pmids":["17065152"],"is_preprint":false},{"year":2011,"finding":"Protein kinase C (PKC) activation downregulates IKs by stimulating dynamin-dependent endocytosis of KCNQ1-KCNE1 complexes. The effect requires phosphorylation of KCNE1 at serine 102; the KCNE1-S102A mutation abolishes PKC-induced endocytosis and current reduction. This mechanism was confirmed in neonatal mouse ventricular myocytes.","method":"Patch clamping; fluorescence microscopy with transferrin endosome colocalization; dominant-negative dynamin (K44A); site-directed mutagenesis (S102A); neonatal mouse myocytes","journal":"Heart rhythm","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, dominant-negative approach, phospho-null mutation, and native cardiomyocyte confirmation","pmids":["21699843"],"is_preprint":false},{"year":2013,"finding":"KCNE1 and KCNE2 undergo sequential proteolytic cleavage: first by either alpha-secretase or BACE1, then by presenilin/gamma-secretase, generating C-terminal fragments and intracellular domains. Elevated BACE1 activity increases KCNE1 processing and shifts the KCNE1/KCNQ1 channel activation curve to more positive potentials, decreasing cardiac repolarization efficiency.","method":"Biochemical CTF detection in HEK293T, B104 neuroblastoma cells, cardiomyocytes, and primary neurons; secretase inhibitors; BACE1 overexpression; electrophysiology","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple cell types, pharmacological and genetic manipulation of secretases, functional electrophysiological readout in same study","pmids":["23504710"],"is_preprint":false},{"year":2010,"finding":"The KCNE1 C-terminal cytoplasmic domain forms a protein-protein interaction with the KCNQ1 S6 activation gate and S4-S5 linker. Cysteine cross-linking identified three KCNQ1 residues (H363C, P369C, I257C) that form disulfide bonds with KCNE1 C-terminal cysteine residues; these interactions are state-dependent (primarily in closed state) and slow activation gate opening.","method":"Cysteine cross-linking (disulfide bond formation); electrophysiology; biochemical screening of >300 cysteine pairs","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic cysteine cross-linking with state-dependent functional validation; large-scale screening with statistical analysis","pmids":["20479109"],"is_preprint":false},{"year":2014,"finding":"KCNE1 divides voltage sensor (S4) movement in KCNQ1/KCNE1 channels into two steps: first, independent movement of each S4 (generating main gating charge, underlying activation delay); second, a slower concerted conformational change of all four voltage sensors and the gate that opens the channel. KCNE1 thus mechanistically uncouples these two steps with different voltage dependences.","method":"Voltage clamp fluorometry; S4 mutagenesis; pharmacological isolation of gating steps","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — voltage clamp fluorometry directly reports voltage sensor movement independently of current; mutagenesis and pharmacology used orthogonally","pmids":["24769622"],"is_preprint":false},{"year":2014,"finding":"LQT mutations at the KCNQ1 helix C / KCNE1 distal C-terminus intracellular interface disrupt KCNQ1-KCNE1 subunit interaction. KCNQ1 helix C mutations impair PIP2 modulation (decreased current density and depolarizing activation shift), while KCNE1 C-terminus mutation P127T suppresses yotiao-dependent cAMP/PKA upregulation of IKs by reducing KCNQ1 S27 phosphorylation.","method":"Co-immunoprecipitation; electrophysiology; mutagenesis; PKA phosphorylation assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, multiple mutations, PKA phosphorylation biochemistry, electrophysiological phenotyping in single study","pmids":["25037568"],"is_preprint":false},{"year":2017,"finding":"KCNE1 affects both the first S4 movement and the gate of KCNQ1, whereas KCNE3 primarily affects S4 movement and only affects the gate if S4-to-gate coupling is intact. A triple mutation in the KCNE3 transmembrane segment middle region introduced KCNE1-like effects on S4 movement and gating, mapping the functional divergence of KCNE1 and KCNE3 to specific transmembrane residues.","method":"Voltage clamp fluorometry; S4 mutagenesis; PIP2 depletion to separate S4 movement from gate opening","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — voltage clamp fluorometry directly measures voltage sensor movements; orthogonal genetic and pharmacological perturbations in single rigorous study","pmids":["28808020"],"is_preprint":false},{"year":1991,"finding":"KCNE1 (IsK) protein localizes specifically to the endolymphatic (apical/luminal) surface of strial marginal cells in the cochlea, as determined by immunohistochemistry with two distinct antibodies, suggesting a direct role in K+ permeation at the luminal membrane.","method":"Immunohistochemistry with two antibodies targeting distinct epitopes of the Isk protein","journal":"Hearing research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization by immunohistochemistry with two independent antibodies; functional consequence inferred from location","pmids":["1663105"],"is_preprint":false},{"year":1997,"finding":"The IsK protein modulates both pharmacological sensitivity and activator responses of the IKs channel: IKs blockers (293B, azimilide, 17β-estradiol) have 6–100-fold higher affinity for KvLQT1/IsK heteromers than KvLQT1 alone. IKs activators (mefenamic acid, DIDS) dramatically enhance heteromeric IKs by arresting channels in an open state, but have little effect on KvLQT1 homomers, demonstrating a direct IsK-dependent pharmacological mechanism.","method":"Heterologous coexpression in Xenopus oocytes; electrophysiology; pharmacological profiling","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct pharmacological comparison of homomeric vs. heteromeric channels; multiple drug classes tested","pmids":["9313924"],"is_preprint":false},{"year":1998,"finding":"IsK/KCNE1 knockout mice exhibit a steeper QT-RR relationship and longer QT intervals at slow heart rates, indicating that the isk gene product blunts QT adaptation to heart rate variations. The absence of IKs leads to a paradoxically shorter QT at fast rates, revealing the channel's role in rate-dependent repolarization reserve.","method":"ECG recordings in isk-/- mice; comparison with wild-type; cellular electrophysiology","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with in vivo electrocardiographic phenotype; functionally informative at both whole-animal and cellular levels; replicated in separate knockout lines","pmids":["9670922"],"is_preprint":false},{"year":2005,"finding":"KCNE1-null mice spontaneously develop atrial fibrillation associated with shortened atrial action potentials and increased outward K+ currents (including KCNQ1-sensitive currents) in atrial myocytes. At rapid pacing rates, IKs (KCNQ1+KCNE1) does not accumulate due to sigmoidal activation, whereas KCNQ1 alone accumulates markedly, explaining the paradoxical increase in outward current with KCNE1 deletion.","method":"KCNE1-null mouse model; in vivo ECG; patch clamp of atrial myocytes; isoproterenol and vagomimetic pharmacology; CHO cell electrophysiology","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic model with in vivo arrhythmia phenotype and mechanistic dissection by patch clamp and pharmacology","pmids":["15947250"],"is_preprint":false},{"year":1999,"finding":"Stilbene and fenamate IKs activators bind to an extracellular domain flanking the IsK transmembrane segment and rescue dominant-negative loss-of-function in IsK C-terminal mutants, including the naturally occurring LQT5 mutant D76N, by restoring slow activation gating. This reveals allosteric interactions between extracellular/intracellular boundaries of the IsK transmembrane segment and between alpha and beta subunit domains.","method":"Mutagenesis; Xenopus oocyte electrophysiology; pharmacological rescue with stilbenes and fenamates","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological rescue of specific mutants with mutagenesis, identifying binding domain; single lab","pmids":["10428953"],"is_preprint":false},{"year":2002,"finding":"SGK1, SGK2, SGK3, and protein kinase B (PKB) all stimulate KCNE1/KCNQ1 channel activity in Xenopus oocytes; kinase-dead SGK1 (K127N) had no effect. The stimulation is independent of Na+/K+-ATPase, establishing serum/glucocorticoid-inducible kinases as direct upstream regulators of KCNE1-dependent K+ channel activity.","method":"Xenopus oocyte two-electrode voltage clamp; coexpression of wild-type, constitutively active, and kinase-dead SGK isoforms","journal":"Pflugers Archiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dead negative control confirms kinase-dependent mechanism; multiple kinase isoforms tested","pmids":["12634932"],"is_preprint":false},{"year":2011,"finding":"AMP-activated protein kinase (AMPK) reduces KCNQ1/KCNE1-mediated currents and decreases KCNQ1 plasma membrane abundance, likely via the ubiquitin ligase Nedd4-2. Nedd4-2 mimicked AMPK's effect. This establishes AMPK as a negative regulator of IKs channel surface expression.","method":"Xenopus oocyte voltage clamp; constitutively active and wild-type AMPK coexpression; Nedd4-2 coexpression; immunostaining and confocal imaging of KCNQ1 membrane abundance","journal":"Molecular membrane biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional and imaging endpoints; constitutively active kinase construct; Nedd4-2 epistasis tested; single lab","pmids":["21231794"],"is_preprint":false},{"year":2010,"finding":"KCNE1 disrupts electrostatic interactions of the C-terminal half of KCNQ1 S4 (S4-C) with the lower conserved glutamate in S2 (Glu170), altering packing around S4 and thereby affecting voltage-dependent gating. Tryptophan scanning of S4 revealed a cluster of S4-C residues where mutations abolish current in the presence of KCNE1.","method":"S4 tryptophan scanning mutagenesis; cysteine accessibility and MTS modification; electrophysiology in presence/absence of KCNE1","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with functional readout; KCNE1-dependent effects specifically mapped to S4-C residues; single lab","pmids":["21112284"],"is_preprint":false},{"year":2001,"finding":"ERG1 (KCNH2) coimmunoprecipitates with KCNE1 in horse heart tissue, providing direct biochemical evidence for KCNE1 association with the HERG channel complex in native cardiac tissue.","method":"Co-immunoprecipitation from native horse heart tissue; immunoblotting; RT-PCR","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP from native tissue with multiple confirmatory methods; single species/lab","pmids":["12063283"],"is_preprint":false},{"year":2009,"finding":"The KCNE1 C-terminus interacts with KCNQ1 to regulate channel assembly, open-state stability, and deactivation kinetics. The LQT5 mutant D76N and full C-terminal truncation (Δ70) both shift voltage dependence, decrease current density, accelerate deactivation, and impair rate-dependent IKs facilitation. C-terminal truncation reduces apparent KCNE1 affinity for KCNQ1, impairing surface delivery of the complex.","method":"Electrophysiology; co-immunoprecipitation; surface expression assays; overexpression titration in heterologous cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional and biochemical methods; two distinct C-terminal mutations with convergent and divergent phenotypes analyzed","pmids":["19340287"],"is_preprint":false},{"year":2008,"finding":"KCNE1 constrains the Kv7.1 voltage sensor by lodging at the inter-VSD S4-S1 interface between adjacent subunits, as revealed by tryptophan scanning mutagenesis of S4 and cysteine engineering. Specific S4 perturbations that mimic KCNE1 effects or compromise KCNE1 regulation mapped to this interface.","method":"Tryptophan-scanning mutagenesis of KCNQ1 S4; cysteine engineering; electrophysiology with and without KCNE1","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — systematic S4 tryptophan scan with functional readout; inter-VSD interface localized by double-mutant analysis; single lab","pmids":["18398469"],"is_preprint":false},{"year":2011,"finding":"Post-translational N-glycosylation of KCNE1 occurs at two sites: one co-translational and one post-translational. Ablation of the co-translational glycosylation site also prevents post-translational glycosylation, resulting in unglycosylated KCNE1 that cannot reach the cell surface with its cognate K+ channel. Engineering the post-translational site into a co-translational context restored monoglycosylation and anterograde trafficking.","method":"Site-directed mutagenesis of glycosylation sites; pulse-chase glycosylation kinetics; cell surface expression assays; mutagenic site conversion","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mechanistic mutagenesis with kinetic glycosylation assays and site conversion rescue; rigorous biogenic mechanism established in single study","pmids":["21676880"],"is_preprint":false},{"year":2014,"finding":"The transmembrane domain of KCNE1 is helical and slightly curved in proteoliposomes (POPC/POPG bilayers), consistent with the solution NMR structure in micelles. DEER distance measurements in three membrane environments confirmed the curvature is maintained in lipid bilayers, supporting its functional relevance.","method":"Double electron-electron resonance (DEER) spectroscopy; simulated annealing MD simulations; comparison across LMPG micelles, proteoliposomes, and lipodisq nanoparticles","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural measurements in physiologically relevant lipid bilayer environment; multiple membrane systems compared orthogonally","pmids":["25234231"],"is_preprint":false},{"year":2016,"finding":"KCNE1 association with KCNQ1 creates fenestrations in the channel that are not present in KCNQ1 alone, providing a binding site for adamantane derivative inhibitors (e.g., JNJ303). These compounds access the channel through KCNE1-dependent fenestrations, enabling highly subtype-specific pharmacological targeting.","method":"Scanning mutagenesis; electrophysiology; chemical ligand modification; chemical cross-linking; MS/MS analysis; molecular modelling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods including cross-linking with MS/MS identification of binding site and structural modeling; mechanistically validated","pmids":["27731317"],"is_preprint":false},{"year":2020,"finding":"KCNE1 fulfils criteria of a bona fide auxiliary subunit of the TMEM16A chloride channel (anoctamin superfamily), in addition to its established role with KCNQ1. KCNE1 assembly with TMEM16A switches channel behavior from calcium-dependent to voltage-dependent. Clinically relevant KCNE1 mutations within the TMEM16A-regulating domain abolish TMEM16A modulation.","method":"Pharmacology; gene invalidation (knockout); single-molecule fluorescence co-assembly assays; electrophysiology with KCNE1 mutants","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including single-molecule fluorescence and gene knockout; clinically relevant mutants tested; novel channel partnership established","pmids":["33373586"],"is_preprint":false},{"year":2012,"finding":"KCNQ1 residue V141 (in S1) is in direct physical proximity to KCNE1 as shown by disulfide cross-linking: V141C forms disulfide bonds with cysteine-substituted KCNE1 residues, while adjacent S140C does not. This structural difference explains the differential KCNE1 dependence of two familial atrial fibrillation mutations (V141M vs. S140G) and maps the KCNE1-KCNQ1 S1 interaction interface.","method":"Disulfide cross-linking; electrophysiology; KCNE1-dependence analysis in Xenopus oocytes","journal":"The Journal of general physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cross-linking directly establishes proximity; functional correlation to KCNE1 dependence; single lab","pmids":["22250012"],"is_preprint":false},{"year":2024,"finding":"Saturation mutagenesis variant effect mapping of all KCNE1 single-amino-acid variants revealed that most functionally deleterious variants affect channel gating rather than surface trafficking. Residues at positions 56-104 are dispensable for trafficking but essential for function. 73% of residues highly intolerant to variation are predicted to contact KCNQ1 or calmodulin, identifying these interfaces as critical for KCNE1 function.","method":"Saturation mutagenesis coupled with high-throughput sequencing (variant effect mapping); cell surface expression assay; functional IKs assay; validated against gold-standard electrophysiology","journal":"Genome medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — comprehensive mutagenesis of 2554+ variants with two independent functional readouts; validated against electrophysiology gold standard","pmids":["38816749"],"is_preprint":false},{"year":1994,"finding":"Protein kinase C (PKC) enhancement or inhibition of IsK channel current is determined by specific cytoplasmic residues. Guinea pig IsK (with serine at position 102 context) shows PKC-enhanced current amplitude mimicking native IKs; mutagenesis of four cytoplasmic amino acids converts the PKC response from enhancement to inhibition, mapping the PKC regulatory site to the intracellular C-terminal domain.","method":"Mutagenesis; Xenopus oocyte electrophysiology; phorbol ester activation of PKC","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis identifies specific cytoplasmic residues; functional phenotype reversal confirms mechanism; single lab","pmids":["7510407"],"is_preprint":false},{"year":2001,"finding":"KCNE1 (IsK) and KCNQ1 (KvLQT1) co-localize at the apical membrane of vestibular dark cells in a polarized fashion, as demonstrated by immunocytochemistry in wild-type and kcne1-/- mice. KCNE1-null mice develop progressive vestibular epithelial degeneration and endolymphatic space collapse, establishing KCNE1 as required for dark-cell endolymph homeostasis.","method":"In situ hybridization; RT-PCR; immunocytochemistry; ultrastructural analysis of kcne1-/- mice","journal":"Hearing research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple imaging modalities; genetic knockout phenotype; co-localization confirmed at cellular level; replicated across multiple inner ear studies","pmids":["11223304"],"is_preprint":false}],"current_model":"KCNE1 (minK/IsK) is a single-transmembrane beta-subunit that obligatorily coassembles with KCNQ1 to form the cardiac slow delayed-rectifier IKs channel complex, with variable stoichiometry (up to 4:4); KCNE1 slows KCNQ1 activation by restraining S4 voltage-sensor movement in two sequential steps and interacting with the S4-S5 linker and S6 gate, enhances conductance by stabilizing the open state via a gain-of-function cleft, and is regulated post-translationally by N-glycosylation, PKA (anchored via AKAPs/yotiao), PKC (phospho-S102 triggering dynamin-dependent endocytosis), SGK, AMPK (via Nedd4-2), PIP2, and BACE1/gamma-secretase cleavage; in the inner ear KCNE1 localizes apically on strial marginal cells and vestibular dark cells where it is essential for K+ secretion into endolymph; KCNE1 also functions as an auxiliary subunit of TMEM16A chloride channels, switching them from calcium-dependent to voltage-dependent gating."},"narrative":{"mechanistic_narrative":"KCNE1 (minK/IsK) is a single-transmembrane auxiliary β-subunit that obligatorily coassembles with the KCNQ1 (KvLQT1) α-subunit to reconstitute the cardiac slow delayed-rectifier potassium current IKs [PMID:8900283]. Its short transmembrane domain, with the immediately C-terminal cytoplasmic region, is sufficient and necessary for channel activity, and KCNE1 behaves as an integral component of the channel that sets gating rather than a passive accessory [PMID:1939241]; its transmembrane helix adopts a curved conformation maintained in lipid bilayers [PMID:18611041, PMID:25234231]. KCNE1 slows KCNQ1 activation through defined structural contacts: it lodges at the inter-voltage-sensor S4-S1 interface and disrupts S4-C/S2 electrostatic packing to restrain voltage-sensor movement [PMID:18398469, PMID:21112284], its C-terminus engages the S6 activation gate and S4-S5 linker via state-dependent (closed-state) interactions that slow gate opening [PMID:20479109], and it splits S4 motion into an initial independent step and a slower concerted gating step, thereby uncoupling charge movement from pore opening [PMID:24769622, PMID:28808020]. Up to four KCNE1 subunits associate with the four KCNQ1 subunits, and gating and voltage dependence scale with the KCNQ1:KCNE1 ratio, allowing stoichiometry to tune repolarization [PMID:20962273]. The channel is further controlled by PIP2 [PMID:15746441] and by an extensive regulatory network acting on trafficking and gating: AKAP/yotiao-anchored PKA upregulation [PMID:11299204, PMID:25037568], PKC-driven endocytosis requiring KCNE1 phosphorylation at Ser102 [PMID:21699843, PMID:7510407], SGK/PKB stimulation [PMID:12634932], AMPK/Nedd4-2-dependent surface downregulation [PMID:21231794], Rab5/Rab11 endocytic recycling [PMID:17293474], obligate co-assembly-dependent secretory trafficking [PMID:17065152], two-site N-glycosylation [PMID:21676880], and sequential BACE1/γ-secretase cleavage [PMID:23504710]. KCNE1 also serves as a cofactor for the HERG/IKr (KCNH2) channel [PMID:10400998, PMID:12063283] and as a bona fide auxiliary subunit of the TMEM16A chloride channel, switching it from calcium-dependent to voltage-dependent gating [PMID:33373586]. Beyond the heart, KCNE1 localizes to the apical membrane of strial marginal and vestibular dark cells where it is required for transepithelial K+ secretion and endolymph homeostasis [PMID:8982171, PMID:1663105, PMID:11223304], and KCNE1 variants cause the LQT5 long-QT syndrome through gating, trafficking, and subunit-interface defects [PMID:10400998, PMID:38816749].","teleology":[{"year":1991,"claim":"Established that the minimal IsK transmembrane domain and the adjacent cytoplasmic region are sufficient and necessary for K+ channel activity, framing IsK as an integral pore-shaping element rather than a passive accessory.","evidence":"Truncation and site-directed mutagenesis with Xenopus oocyte electrophysiology","pmids":["1939241"],"confidence":"High","gaps":["Identity of the partner α-subunit not yet known","No structural basis for gating effects"]},{"year":1991,"claim":"Localized IsK protein to the apical/endolymphatic surface of cochlear strial marginal cells, first connecting the protein to inner-ear K+ handling.","evidence":"Immunohistochemistry with two distinct anti-IsK antibodies","pmids":["1663105"],"confidence":"Medium","gaps":["Functional role inferred from location only","No genetic loss-of-function evidence yet"]},{"year":1993,"claim":"Reported that IsK expression induces a Cl-selective current alongside K+ current, with separable N- and C-terminal determinants, raising the model of IsK as a regulator of distinct endogenous channels.","evidence":"Site-directed mutagenesis and Xenopus oocyte electrophysiology","pmids":["8413671"],"confidence":"Medium","gaps":["Identity of the Cl- channel not resolved","Endogenous oocyte channel contribution unclear"]},{"year":1996,"claim":"Identified the obligate α-subunit partner: coexpression of KCNE1 with KCNQ1 reconstitutes native cardiac IKs, defining the molecular composition of the slow delayed rectifier.","evidence":"Heterologous coexpression in Xenopus oocytes with electrophysiology","pmids":["8900283"],"confidence":"High","gaps":["Stoichiometry of the complex unknown","Mechanism of activation slowing not defined"]},{"year":1996,"claim":"Demonstrated genetically that IsK is required for transepithelial K+ secretion into endolymph, establishing its physiological role in inner-ear epithelia.","evidence":"IsK knockout mouse with short-circuit current measurement of inner-ear epithelia","pmids":["8982171"],"confidence":"High","gaps":["Identity of the secretory channel partner in vivo not addressed here","Cardiac consequences not measured in same study"]},{"year":1998,"claim":"Showed in vivo that IsK blunts QT adaptation to heart rate, defining IKs as a contributor to rate-dependent repolarization reserve.","evidence":"ECG and cellular electrophysiology in isk-/- mice","pmids":["9670922"],"confidence":"High","gaps":["Atrial versus ventricular contribution not separated","Molecular basis of rate dependence not yet mechanistic"]},{"year":1994,"claim":"Mapped the PKC regulatory response of IsK to specific cytoplasmic C-terminal residues, showing intracellular determinants set whether PKC enhances or inhibits current.","evidence":"Mutagenesis and phorbol-ester PKC activation in Xenopus oocytes","pmids":["7510407"],"confidence":"Medium","gaps":["Direct phosphorylation site not pinpointed in this study","Native cardiomyocyte relevance not tested"]},{"year":1997,"claim":"Demonstrated that IsK confers distinct pharmacological sensitivity on the IKs heteromer, showing blockers and activators act through an IsK-dependent mechanism on the open state.","evidence":"Pharmacological profiling of homomeric vs heteromeric channels in Xenopus oocytes","pmids":["9313924"],"confidence":"Medium","gaps":["Drug binding site not localized","Single expression system"]},{"year":1999,"claim":"Defined KCNE1 as a co-factor for both IKs and IKr by characterizing LQT5 mutants with divergent trafficking and gating defects.","evidence":"Electrophysiology and surface immunocytochemistry of LQT5 mutants in oocytes and HEK293","pmids":["10400998"],"confidence":"High","gaps":["Native IKr association not yet shown biochemically","Structural interface with HERG undefined"]},{"year":1999,"claim":"Localized stilbene/fenamate activator binding to an extracellular domain flanking the IsK transmembrane segment and showed pharmacological rescue of LQT5 mutants, revealing allosteric α-β coupling.","evidence":"Mutagenesis and pharmacological rescue in Xenopus oocytes","pmids":["10428953"],"confidence":"Medium","gaps":["Precise binding residues not resolved","Single lab"]},{"year":2001,"claim":"Established that cAMP/PKA upregulation of IKs requires PKA anchoring to the channel via AKAPs, linking adrenergic signaling to the complex.","evidence":"AKAP coexpression and Ht31 disruption with whole-cell patch clamp","pmids":["11299204"],"confidence":"High","gaps":["Phosphorylation target residue not mapped here","Native cardiomyocyte AKAP identity not defined"]},{"year":2001,"claim":"Provided biochemical evidence in native cardiac tissue that KCNE1 associates with ERG1/HERG, supporting a physical KCNE1-IKr partnership in vivo.","evidence":"Co-immunoprecipitation and RT-PCR from horse heart tissue","pmids":["12063283"],"confidence":"Medium","gaps":["Single species and lab","Functional stoichiometry of KCNE1-HERG not defined"]},{"year":2001,"claim":"Demonstrated KCNQ1/KCNE1 co-localization at vestibular dark-cell apical membranes and that KCNE1 loss causes epithelial degeneration and endolymphatic collapse.","evidence":"In situ hybridization, immunocytochemistry, and ultrastructure of kcne1-/- mice","pmids":["11223304"],"confidence":"High","gaps":["Degeneration mechanism downstream of K+ secretion failure not defined"]},{"year":2002,"claim":"Identified SGK isoforms and PKB as direct upstream stimulators of KCNE1/KCNQ1 activity independent of Na+/K+-ATPase.","evidence":"Coexpression of wild-type, constitutively active, and kinase-dead SGK with two-electrode voltage clamp","pmids":["12634932"],"confidence":"Medium","gaps":["Direct channel phosphorylation vs trafficking mechanism not distinguished here","Single system"]},{"year":2005,"claim":"Showed PIP2 directly regulates the complex and that LQT KCNQ1 mutations act by reducing PIP2 affinity, establishing impaired lipid interaction as a disease mechanism.","evidence":"Giant excised patch electrophysiology, direct PIP2 application, MTSET chemical rescue, and PIP2 binding assay","pmids":["15746441"],"confidence":"High","gaps":["KCNE1's specific contribution to the PIP2 site not isolated","Structural PIP2 binding site not resolved"]},{"year":2005,"claim":"Revealed that KCNE1 loss produces atrial fibrillation through paradoxical increases in outward K+ current, explaining how sigmoidal IKs activation prevents accumulation at fast rates.","evidence":"KCNE1-null mouse ECG, atrial myocyte patch clamp, and CHO electrophysiology","pmids":["15947250"],"confidence":"High","gaps":["Human atrial relevance not directly tested","Chamber-specific KCNE1 stoichiometry not measured"]},{"year":2006,"claim":"Established that KCNE1 requires co-assembly with α-subunits to exit the early secretory pathway, defining co-assembly-dependent forward trafficking.","evidence":"Deglycosylation, immunofluorescence, and quantitative surface labeling in multiple cell lines","pmids":["17065152"],"confidence":"High","gaps":["ER quality-control machinery retaining unassembled KCNE1 not identified"]},{"year":2007,"claim":"Defined endocytic recycling of the complex through Rab5/Rab11 and SGK1-driven exocytosis via PI(3,5)P2, providing a mechanism for stress-accelerated repolarization.","evidence":"Dominant-negative Rab constructs, pharmacology, biochemical trafficking assays, and electrophysiology","pmids":["17293474"],"confidence":"High","gaps":["In vivo cardiac relevance of the recycling pathway not established"]},{"year":2008,"claim":"Determined the KCNE1 NMR structure and modeled how it contacts the S4-S5 linker in the closed state and a gain-of-function cleft in the open state to slow activation and raise conductance.","evidence":"Solution NMR structure with restrained docking to KCNQ1 and functional validation","pmids":["18611041"],"confidence":"High","gaps":["Structure solved in micelles, not the full assembled complex","Docking model not directly visualized"]},{"year":2008,"claim":"Mapped KCNE1 to the inter-VSD S4-S1 interface between adjacent subunits where it constrains the Kv7.1 voltage sensor.","evidence":"Tryptophan-scanning mutagenesis of KCNQ1 S4 and cysteine engineering with electrophysiology","pmids":["18398469"],"confidence":"Medium","gaps":["Single lab","Direct cross-link to KCNE1 residues not shown here"]},{"year":2009,"claim":"Established the KCNE1 C-terminus as a regulator of assembly, open-state stability, deactivation, and rate-dependent facilitation, with LQT5 D76N and C-terminal truncation impairing affinity and surface delivery.","evidence":"Electrophysiology, co-IP, surface expression, and overexpression titration","pmids":["19340287"],"confidence":"Medium","gaps":["Atomic-level C-terminal interaction interface not resolved","Single lab"]},{"year":2010,"claim":"Quantified flexible up-to-4:4 stoichiometry and showed gating depends on KCNQ1:KCNE1 ratio, indicating expression-level control of repolarization.","evidence":"Single-molecule fluorescence subunit counting with ratio-varied electrophysiology","pmids":["20962273"],"confidence":"High","gaps":["In vivo stoichiometry in cardiomyocytes not measured"]},{"year":2010,"claim":"Identified state-dependent disulfide contacts between the KCNE1 C-terminus and the KCNQ1 S6 gate and S4-S5 linker, providing a direct structural basis for slowed gate opening.","evidence":"Cysteine cross-linking screen of >300 pairs with electrophysiology","pmids":["20479109"],"confidence":"High","gaps":["Dynamics of the interaction during gating not resolved"]},{"year":2010,"claim":"Showed KCNE1 disrupts S4-C/S2 (Glu170) electrostatic interactions, altering S4 packing to shape voltage-dependent gating.","evidence":"S4 tryptophan scanning, cysteine accessibility/MTS modification, and electrophysiology","pmids":["21112284"],"confidence":"Medium","gaps":["Single lab","Effect on individual gating transitions not fully separated"]},{"year":2011,"claim":"Identified two-site N-glycosylation of KCNE1, with a co-translational site governing a subsequent post-translational site and overall surface trafficking competence.","evidence":"Glycosylation-site mutagenesis, pulse-chase kinetics, surface assays, and site-conversion rescue","pmids":["21676880"],"confidence":"High","gaps":["Functional consequence of glycosylation state on gating not addressed"]},{"year":2011,"claim":"Defined PKC-induced dynamin-dependent endocytosis of the complex requiring KCNE1 Ser102 phosphorylation, confirmed in native cardiomyocytes.","evidence":"Patch clamp, transferrin colocalization, dominant-negative dynamin K44A, S102A mutation, neonatal mouse myocytes","pmids":["21699843"],"confidence":"High","gaps":["Upstream PKC isoform identity not specified","Adult myocyte relevance not tested"]},{"year":2011,"claim":"Established AMPK as a negative regulator of IKs surface abundance acting through Nedd4-2.","evidence":"Constitutively active AMPK and Nedd4-2 coexpression with voltage clamp and confocal imaging in oocytes","pmids":["21231794"],"confidence":"Medium","gaps":["Direct ubiquitination site not mapped","Single heterologous system"]},{"year":2012,"claim":"Pinpointed KCNQ1 S1 residue V141 in direct proximity to KCNE1, explaining differential KCNE1-dependence of familial atrial fibrillation mutations.","evidence":"Disulfide cross-linking and KCNE1-dependence analysis in Xenopus oocytes","pmids":["22250012"],"confidence":"Medium","gaps":["Single lab","Full S1 interaction surface not mapped"]},{"year":2013,"claim":"Showed KCNE1 undergoes sequential α/BACE1 then γ-secretase cleavage, with elevated BACE1 shifting channel activation positively and impairing repolarization.","evidence":"CTF biochemistry across multiple cell types, secretase inhibitors, BACE1 overexpression, and electrophysiology","pmids":["23504710"],"confidence":"High","gaps":["Physiological trigger of cleavage in heart not established","Fate/function of released fragments unknown"]},{"year":2014,"claim":"Demonstrated KCNE1 splits S4 movement into an early independent step and a slower concerted gating step, mechanistically uncoupling charge movement from pore opening.","evidence":"Voltage clamp fluorometry, S4 mutagenesis, and pharmacological isolation of gating steps","pmids":["24769622"],"confidence":"High","gaps":["Structural correlate of the two-step model not visualized"]},{"year":2014,"claim":"Identified an intracellular KCNQ1 helix C / KCNE1 distal C-terminus interface whose mutations disrupt PIP2 modulation and yotiao-dependent PKA upregulation, integrating gating, lipid, and signaling control.","evidence":"Co-IP, electrophysiology, mutagenesis, and PKA phosphorylation assays","pmids":["25037568"],"confidence":"High","gaps":["Atomic structure of the helix C interface not resolved"]},{"year":2017,"claim":"Distinguished KCNE1 from KCNE3 mechanistically, showing KCNE1 affects both the first S4 movement and the gate, and mapped the divergence to specific transmembrane residues.","evidence":"Voltage clamp fluorometry, S4 mutagenesis, and PIP2 depletion in Xenopus oocytes","pmids":["28808020"],"confidence":"High","gaps":["Structural basis of transmembrane residue effects not visualized"]},{"year":2016,"claim":"Showed KCNE1 assembly creates channel fenestrations absent in KCNQ1 alone, providing an adamantane (JNJ303) binding site and a route to subtype-selective pharmacology.","evidence":"Scanning mutagenesis, electrophysiology, chemical cross-linking with MS/MS, and molecular modeling","pmids":["27731317"],"confidence":"High","gaps":["High-resolution structure of the fenestration-drug complex not determined"]},{"year":2020,"claim":"Established KCNE1 as a bona fide auxiliary subunit of the TMEM16A chloride channel, switching it from calcium-dependent to voltage-dependent gating, expanding its role beyond K+ channels.","evidence":"Pharmacology, gene knockout, single-molecule co-assembly assays, and electrophysiology with KCNE1 mutants","pmids":["33373586"],"confidence":"High","gaps":["Physiological tissue context of KCNE1-TMEM16A not defined","Structure of the assembly not resolved"]},{"year":2024,"claim":"Mapped the functional consequences of all KCNE1 single-amino-acid variants, showing most deleterious variants affect gating rather than trafficking and concentrate at KCNQ1/calmodulin contact interfaces.","evidence":"Saturation mutagenesis variant effect mapping with surface and IKs functional readouts validated against electrophysiology","pmids":["38816749"],"confidence":"High","gaps":["Calmodulin interaction not directly biochemically characterized in this corpus","In vivo penetrance of variants not addressed"]},{"year":null,"claim":"How KCNE1 stoichiometry, post-translational modification, and partner choice (KCNQ1 vs HERG vs TMEM16A) are coordinated in native tissues to set repolarization and secretion remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of an assembled KCNE1-containing channel complex in the corpus","In vivo stoichiometry and partner partitioning not quantified","Direct KCNE1-calmodulin interaction not biochemically defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4,14,31]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[10,11,17,35]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[10,28]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[7,11]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,17,35]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,11,22]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[7,10,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,8,33]}],"complexes":["KCNQ1-KCNE1 (IKs) channel","KCNH2/HERG (IKr) channel","TMEM16A chloride channel"],"partners":["KCNQ1","KCNH2","TMEM16A","AKAP9/YOTIAO","NEDD4-2","SGK1","BACE1","DNM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P15382","full_name":"Potassium voltage-gated channel subfamily E member 1","aliases":["Delayed rectifier potassium channel subunit IsK","IKs producing slow voltage-gated potassium channel subunit beta Mink","Minimal potassium channel","MinK"],"length_aa":129,"mass_kda":14.7,"function":"Ancillary protein that functions as a regulatory subunit of the voltage-gated potassium (Kv) channel complex composed of pore-forming and potassium-conducting alpha subunits and of regulatory beta subunits. KCNE1 beta subunit modulates the gating kinetics and enhances stability of the channel complex (PubMed:19219384, PubMed:20533308, PubMed:9230439). Alters the gating of the delayed rectifier Kv channel containing KCNB1 alpha subunit (PubMed:19219384). Associates with KCNQ1/KVLQT1 alpha subunit to form the slowly activating delayed rectifier cardiac potassium (IKs) channel responsible for ventricular muscle action potential repolarization (PubMed:20533308). The outward current reaches its steady state only after 50 seconds (Probable). Assembly with KCNH2/HERG alpha subunit Kv channel may regulate the rapidly activating component of the delayed rectifying potassium current (IKr) in heart (PubMed:9230439)","subcellular_location":"Cell membrane; Apical cell membrane; Membrane raft","url":"https://www.uniprot.org/uniprotkb/P15382/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KCNE1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KCNE1","total_profiled":1310},"omim":[{"mim_id":"613695","title":"LONG QT SYNDROME 5; LQT5","url":"https://www.omim.org/entry/613695"},{"mim_id":"613693","title":"LONG QT SYNDROME 6; LQT6","url":"https://www.omim.org/entry/613693"},{"mim_id":"613688","title":"LONG QT SYNDROME 2; LQT2","url":"https://www.omim.org/entry/613688"},{"mim_id":"613035","title":"HEARING LOSS, NOISE-INDUCED, SUSCEPTIBILITY TO; NIHL","url":"https://www.omim.org/entry/613035"},{"mim_id":"612347","title":"JERVELL AND LANGE-NIELSEN SYNDROME 2; JLNS2","url":"https://www.omim.org/entry/612347"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"choroid plexus","ntpm":14.9},{"tissue":"fallopian tube","ntpm":14.4},{"tissue":"heart muscle","ntpm":10.7},{"tissue":"kidney","ntpm":3.9}],"url":"https://www.proteinatlas.org/search/KCNE1"},"hgnc":{"alias_symbol":["minK","IsK","JLNS2","LQT5"],"prev_symbol":[]},"alphafold":{"accession":"P15382","domains":[{"cath_id":"1.20.5","chopping":"38-73","consensus_level":"medium","plddt":83.6506,"start":38,"end":73}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P15382","model_url":"https://alphafold.ebi.ac.uk/files/AF-P15382-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P15382-F1-predicted_aligned_error_v6.png","plddt_mean":70.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KCNE1","jax_strain_url":"https://www.jax.org/strain/search?query=KCNE1"},"sequence":{"accession":"P15382","fasta_url":"https://rest.uniprot.org/uniprotkb/P15382.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P15382/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P15382"}},"corpus_meta":[{"pmid":"8900283","id":"PMC_8900283","title":"Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel.","date":"1996","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/8900283","citation_count":1490,"is_preprint":false},{"pmid":"10973849","id":"PMC_10973849","title":"Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.","date":"2000","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/10973849","citation_count":962,"is_preprint":false},{"pmid":"8982171","id":"PMC_8982171","title":"Inner ear defects induced by null mutation of the isk gene.","date":"1996","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/8982171","citation_count":311,"is_preprint":false},{"pmid":"9328483","id":"PMC_9328483","title":"IsK and KvLQT1: mutation in either of the two subunits of the slow component of the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome.","date":"1997","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9328483","citation_count":248,"is_preprint":false},{"pmid":"2183220","id":"PMC_2183220","title":"Cloning and expression of the delayed-rectifier IsK channel from neonatal rat heart and diethylstilbestrol-primed rat uterus.","date":"1990","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/2183220","citation_count":186,"is_preprint":false},{"pmid":"18611041","id":"PMC_18611041","title":"Structure of KCNE1 and implications for how it modulates the KCNQ1 potassium channel.","date":"2008","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18611041","citation_count":172,"is_preprint":false},{"pmid":"9445165","id":"PMC_9445165","title":"Mutation of the gene for IsK associated with both Jervell and Lange-Nielsen and Romano-Ward forms of Long-QT syndrome.","date":"1998","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/9445165","citation_count":169,"is_preprint":false},{"pmid":"7597086","id":"PMC_7597086","title":"A corticosteroid-induced gene expressing an \"IsK-like\" K+ channel activity in Xenopus oocytes.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7597086","citation_count":161,"is_preprint":false},{"pmid":"20962273","id":"PMC_20962273","title":"Stoichiometry of the KCNQ1 - KCNE1 ion channel complex.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20962273","citation_count":158,"is_preprint":false},{"pmid":"10400998","id":"PMC_10400998","title":"Cellular dysfunction of LQT5-minK mutants: abnormalities of IKs, IKr and trafficking in long QT syndrome.","date":"1999","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10400998","citation_count":137,"is_preprint":false},{"pmid":"17293474","id":"PMC_17293474","title":"Regulation of endocytic recycling of KCNQ1/KCNE1 potassium channels.","date":"2007","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/17293474","citation_count":135,"is_preprint":false},{"pmid":"8413671","id":"PMC_8413671","title":"The protein IsK is a dual activator of K+ and Cl- channels.","date":"1993","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/8413671","citation_count":126,"is_preprint":false},{"pmid":"19695459","id":"PMC_19695459","title":"D85N, a KCNE1 polymorphism, is a disease-causing gene variant in long QT syndrome.","date":"2009","source":"Journal of the American College of Cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/19695459","citation_count":121,"is_preprint":false},{"pmid":"9313924","id":"PMC_9313924","title":"The role of the IsK protein in the specific pharmacological properties of the IKs channel complex.","date":"1997","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/9313924","citation_count":110,"is_preprint":false},{"pmid":"9852064","id":"PMC_9852064","title":"MinK-KvLQT1 fusion proteins, evidence for multiple stoichiometries of the assembled IsK channel.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9852064","citation_count":105,"is_preprint":false},{"pmid":"9670922","id":"PMC_9670922","title":"Involvement of IsK-associated K+ channel in heart rate control of repolarization in a murine engineered model of Jervell and Lange-Nielsen syndrome.","date":"1998","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/9670922","citation_count":104,"is_preprint":false},{"pmid":"11208532","id":"PMC_11208532","title":"Differential expression of KvLQT1 and its regulator IsK in mouse epithelia.","date":"2001","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11208532","citation_count":98,"is_preprint":false},{"pmid":"10728423","id":"PMC_10728423","title":"Novel mutations in KvLQT1 that affect Iks activation through interactions with Isk.","date":"2000","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/10728423","citation_count":98,"is_preprint":false},{"pmid":"1939241","id":"PMC_1939241","title":"Alteration of channel activities and gating by mutations of slow ISK potassium channel.","date":"1991","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1939241","citation_count":96,"is_preprint":false},{"pmid":"15746441","id":"PMC_15746441","title":"Impaired KCNQ1-KCNE1 and phosphatidylinositol-4,5-bisphosphate interaction underlies the long QT syndrome.","date":"2005","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/15746441","citation_count":94,"is_preprint":false},{"pmid":"1663105","id":"PMC_1663105","title":"Cellular localization of rat Isk protein in the stria vascularis by immunohistochemical observation.","date":"1991","source":"Hearing research","url":"https://pubmed.ncbi.nlm.nih.gov/1663105","citation_count":91,"is_preprint":false},{"pmid":"11193411","id":"PMC_11193411","title":"A novel lantibiotic, nukacin ISK-1, of Staphylococcus warneri ISK-1: cloning of the structural gene and identification of the structure.","date":"2000","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11193411","citation_count":85,"is_preprint":false},{"pmid":"11223304","id":"PMC_11223304","title":"KCNQ1/KCNE1 potassium channels in mammalian vestibular dark cells.","date":"2001","source":"Hearing research","url":"https://pubmed.ncbi.nlm.nih.gov/11223304","citation_count":84,"is_preprint":false},{"pmid":"12634932","id":"PMC_12634932","title":"Regulation of KCNE1-dependent K(+) current by the serum and glucocorticoid-inducible kinase (SGK) isoforms.","date":"2002","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12634932","citation_count":81,"is_preprint":false},{"pmid":"24769622","id":"PMC_24769622","title":"KCNE1 divides the voltage sensor movement in KCNQ1/KCNE1 channels into two steps.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24769622","citation_count":76,"is_preprint":false},{"pmid":"10428953","id":"PMC_10428953","title":"Stilbenes and fenamates rescue the loss of I(KS) channel function induced by an LQT5 mutation and other IsK mutants.","date":"1999","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/10428953","citation_count":75,"is_preprint":false},{"pmid":"26410412","id":"PMC_26410412","title":"KCNE1 and KCNE3: The yin and yang of voltage-gated K(+) channel regulation.","date":"2015","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/26410412","citation_count":71,"is_preprint":false},{"pmid":"15947250","id":"PMC_15947250","title":"Atrial fibrillation in KCNE1-null mice.","date":"2005","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/15947250","citation_count":70,"is_preprint":false},{"pmid":"24386485","id":"PMC_24386485","title":"MicroRNA-1 accelerates the shortening of atrial effective refractory period by regulating KCNE1 and KCNB2 expression: an atrial tachypacing rabbit model.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24386485","citation_count":70,"is_preprint":false},{"pmid":"12063283","id":"PMC_12063283","title":"Expression and coassociation of ERG1, KCNQ1, and KCNE1 potassium channel proteins in horse heart.","date":"2002","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12063283","citation_count":69,"is_preprint":false},{"pmid":"7969055","id":"PMC_7969055","title":"Positive regulation by chloride channel blockers of IsK channels expressed in Xenopus oocytes.","date":"1994","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/7969055","citation_count":65,"is_preprint":false},{"pmid":"10493825","id":"PMC_10493825","title":"KCNE1-like gene is deleted in AMME contiguous gene syndrome: identification and characterization of the human and mouse homologs.","date":"1999","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10493825","citation_count":64,"is_preprint":false},{"pmid":"11320260","id":"PMC_11320260","title":"Distinct gene-specific mechanisms of arrhythmia revealed by cardiac gene transfer of two long QT disease genes, HERG and KCNE1.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11320260","citation_count":59,"is_preprint":false},{"pmid":"22329487","id":"PMC_22329487","title":"Ring A of nukacin ISK-1: a lipid II-binding motif for type-A(II) lantibiotic.","date":"2012","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/22329487","citation_count":58,"is_preprint":false},{"pmid":"16143300","id":"PMC_16143300","title":"Lanthionine introduction into nukacin ISK-1 prepeptide by co-expression with modification enzyme NukM in Escherichia coli.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16143300","citation_count":57,"is_preprint":false},{"pmid":"11299204","id":"PMC_11299204","title":"AKAP proteins anchor cAMP-dependent protein kinase to KvLQT1/IsK channel complex.","date":"2001","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11299204","citation_count":55,"is_preprint":false},{"pmid":"11832382","id":"PMC_11832382","title":"The multifaceted phenotype of the knockout mouse for the KCNE1 potassium channel gene.","date":"2002","source":"American journal of physiology. Regulatory, integrative and comparative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11832382","citation_count":55,"is_preprint":false},{"pmid":"17065152","id":"PMC_17065152","title":"KCNE1 subunits require co-assembly with K+ channels for efficient trafficking and cell surface expression.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17065152","citation_count":54,"is_preprint":false},{"pmid":"17892302","id":"PMC_17892302","title":"Preparation, functional characterization, and NMR studies of human KCNE1, a voltage-gated potassium channel accessory subunit associated with deafness and long QT syndrome.","date":"2007","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17892302","citation_count":54,"is_preprint":false},{"pmid":"23894484","id":"PMC_23894484","title":"Three distinct two-component systems are involved in resistance to the class I bacteriocins, Nukacin ISK-1 and nisin A, in Staphylococcus aureus.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23894484","citation_count":53,"is_preprint":false},{"pmid":"19372218","id":"PMC_19372218","title":"Dynamic partnership between KCNQ1 and KCNE1 and influence on cardiac IKs current amplitude by KCNE2.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19372218","citation_count":48,"is_preprint":false},{"pmid":"21699843","id":"PMC_21699843","title":"Protein kinase C downregulates I(Ks) by stimulating KCNQ1-KCNE1 potassium channel endocytosis.","date":"2011","source":"Heart rhythm","url":"https://pubmed.ncbi.nlm.nih.gov/21699843","citation_count":47,"is_preprint":false},{"pmid":"28808020","id":"PMC_28808020","title":"KCNE1 and KCNE3 modulate KCNQ1 channels by affecting different gating transitions.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28808020","citation_count":47,"is_preprint":false},{"pmid":"12566121","id":"PMC_12566121","title":"Coordinated down-regulation of KCNQ1 and KCNE1 expression contributes to reduction of I(Ks) in canine hypertrophied hearts.","date":"2003","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/12566121","citation_count":47,"is_preprint":false},{"pmid":"26168993","id":"PMC_26168993","title":"A new KCNQ1 mutation at the S5 segment that impairs its association with KCNE1 is responsible for short QT syndrome.","date":"2015","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/26168993","citation_count":45,"is_preprint":false},{"pmid":"16041148","id":"PMC_16041148","title":"A novel type of immunity protein, NukH, for the lantibiotic nukacin ISK-1 produced by Staphylococcus warneri ISK-1.","date":"2005","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16041148","citation_count":44,"is_preprint":false},{"pmid":"11889581","id":"PMC_11889581","title":"The role of KCNQ1/KCNE1 K(+) channels in intestine and pancreas: lessons from the KCNE1 knockout mouse.","date":"2001","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11889581","citation_count":44,"is_preprint":false},{"pmid":"8081718","id":"PMC_8081718","title":"Are Xenopus oocytes unique in displaying functional IsK channel heterologous expression?","date":"1993","source":"Receptors & channels","url":"https://pubmed.ncbi.nlm.nih.gov/8081718","citation_count":44,"is_preprint":false},{"pmid":"25037568","id":"PMC_25037568","title":"Long QT mutations at the interface between KCNQ1 helix C and KCNE1 disrupt I(KS) regulation by PKA and PIP₂.","date":"2014","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/25037568","citation_count":43,"is_preprint":false},{"pmid":"9396783","id":"PMC_9396783","title":"KvLQT1 potassium channel but not IsK is the molecular target for trans-6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethyl- chromane.","date":"1997","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/9396783","citation_count":42,"is_preprint":false},{"pmid":"9447925","id":"PMC_9447925","title":"cAMP increases K+ secretion via activation of apical IsK/KvLQT1 channels in strial marginal cells.","date":"1997","source":"Hearing research","url":"https://pubmed.ncbi.nlm.nih.gov/9447925","citation_count":42,"is_preprint":false},{"pmid":"19506061","id":"PMC_19506061","title":"Nukacin ISK-1, a bacteriostatic lantibiotic.","date":"2009","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/19506061","citation_count":41,"is_preprint":false},{"pmid":"23504710","id":"PMC_23504710","title":"BACE1 and presenilin/γ-secretase regulate proteolytic processing of KCNE1 and 2, auxiliary subunits of voltage-gated potassium channels.","date":"2013","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/23504710","citation_count":41,"is_preprint":false},{"pmid":"17161791","id":"PMC_17161791","title":"KCNE2 is colocalized with KCNQ1 and KCNE1 in cardiac myocytes and may function as a negative modulator of I(Ks) current amplitude in the heart.","date":"2006","source":"Heart rhythm","url":"https://pubmed.ncbi.nlm.nih.gov/17161791","citation_count":41,"is_preprint":false},{"pmid":"8899564","id":"PMC_8899564","title":"Exclusion of KCNE1 (IsK) as a candidate gene for Jervell and Lange-Nielsen syndrome.","date":"1996","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/8899564","citation_count":40,"is_preprint":false},{"pmid":"20479109","id":"PMC_20479109","title":"Identification of a protein-protein interaction between KCNE1 and the activation gate machinery of KCNQ1.","date":"2010","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/20479109","citation_count":40,"is_preprint":false},{"pmid":"19340287","id":"PMC_19340287","title":"Functional interactions between KCNE1 C-terminus and the KCNQ1 channel.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19340287","citation_count":40,"is_preprint":false},{"pmid":"25234231","id":"PMC_25234231","title":"Structural investigation of the transmembrane domain of KCNE1 in proteoliposomes.","date":"2014","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25234231","citation_count":40,"is_preprint":false},{"pmid":"17341399","id":"PMC_17341399","title":"N- and C-terminal KCNE1 mutations cause distinct phenotypes of long QT syndrome.","date":"2006","source":"Heart rhythm","url":"https://pubmed.ncbi.nlm.nih.gov/17341399","citation_count":40,"is_preprint":false},{"pmid":"18279388","id":"PMC_18279388","title":"KCNE4 can co-associate with the I(Ks) (KCNQ1-KCNE1) channel complex.","date":"2008","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/18279388","citation_count":40,"is_preprint":false},{"pmid":"7943198","id":"PMC_7943198","title":"Differential expression of Isk mRNAs in mouse tissue during development and pregnancy.","date":"1994","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/7943198","citation_count":39,"is_preprint":false},{"pmid":"21112284","id":"PMC_21112284","title":"KCNE1 remodels the voltage sensor of Kv7.1 to modulate channel function.","date":"2010","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/21112284","citation_count":39,"is_preprint":false},{"pmid":"22876232","id":"PMC_22876232","title":"The KCNE Tango - How KCNE1 Interacts with Kv7.1.","date":"2012","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/22876232","citation_count":39,"is_preprint":false},{"pmid":"7510407","id":"PMC_7510407","title":"K+ currents expressed from the guinea pig cardiac IsK protein are enhanced by activators of protein kinase C.","date":"1994","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7510407","citation_count":38,"is_preprint":false},{"pmid":"9435509","id":"PMC_9435509","title":"P2U purinergic receptor inhibits apical IsK/KvLQT1 channel via protein kinase C in vestibular dark cells.","date":"1997","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/9435509","citation_count":37,"is_preprint":false},{"pmid":"21943416","id":"PMC_21943416","title":"KCNE1 and KCNE2 inhibit forward trafficking of homomeric N-type voltage-gated potassium channels.","date":"2011","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/21943416","citation_count":37,"is_preprint":false},{"pmid":"9114727","id":"PMC_9114727","title":"Role of the ISK protein in the IminK channel complex.","date":"1997","source":"Trends in pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/9114727","citation_count":36,"is_preprint":false},{"pmid":"18398469","id":"PMC_18398469","title":"KCNE1 constrains the voltage sensor of Kv7.1 K+ channels.","date":"2008","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/18398469","citation_count":36,"is_preprint":false},{"pmid":"22085289","id":"PMC_22085289","title":"Reconstitution of KCNE1 into lipid bilayers: comparing the structural, dynamic, and activity differences in micelle and vesicle environments.","date":"2011","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22085289","citation_count":36,"is_preprint":false},{"pmid":"17895974","id":"PMC_17895974","title":"Differential association between HERG and KCNE1 or KCNE2.","date":"2007","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/17895974","citation_count":35,"is_preprint":false},{"pmid":"27076034","id":"PMC_27076034","title":"A novel transgenic rabbit model with reduced repolarization reserve: long QT syndrome caused by a dominant-negative mutation of the KCNE1 gene.","date":"2016","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27076034","citation_count":35,"is_preprint":false},{"pmid":"16233732","id":"PMC_16233732","title":"Heterologous expression and functional analysis of the gene cluster for the biosynthesis of and immunity to the lantibiotic, nukacin ISK-1.","date":"2004","source":"Journal of bioscience and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/16233732","citation_count":35,"is_preprint":false},{"pmid":"9745964","id":"PMC_9745964","title":"Divalent cations inhibit IsK/KvLQT1 channels in excised membrane patches of strial marginal cells.","date":"1998","source":"Hearing research","url":"https://pubmed.ncbi.nlm.nih.gov/9745964","citation_count":35,"is_preprint":false},{"pmid":"9790991","id":"PMC_9790991","title":"Adult KCNE1-knockout mice exhibit a mild cardiac cellular phenotype.","date":"1998","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9790991","citation_count":34,"is_preprint":false},{"pmid":"32581825","id":"PMC_32581825","title":"Gating and Regulation of KCNQ1 and KCNQ1 + KCNE1 Channel Complexes.","date":"2020","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32581825","citation_count":33,"is_preprint":false},{"pmid":"16909339","id":"PMC_16909339","title":"Characterization of recombinant human cardiac KCNQ1/KCNE1 channels (I (Ks)) stably expressed in HEK 293 cells.","date":"2006","source":"The Journal of membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/16909339","citation_count":33,"is_preprint":false},{"pmid":"7876101","id":"PMC_7876101","title":"Molecular basis of IsK protein regulation by oxidation or chelation.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7876101","citation_count":32,"is_preprint":false},{"pmid":"8621512","id":"PMC_8621512","title":"Cytoplasmic and extracellular IsK peptides activate endogenous K+ and Cl- channels in Xenopus oocytes. Evidence for regulatory function.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8621512","citation_count":32,"is_preprint":false},{"pmid":"23709506","id":"PMC_23709506","title":"Involvement of the novel two-component NsrRS and LcrRS systems in distinct resistance pathways against nisin A and nukacin ISK-1 in Streptococcus mutans.","date":"2013","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/23709506","citation_count":31,"is_preprint":false},{"pmid":"15322349","id":"PMC_15322349","title":"Characterization of a gene cluster of Staphylococcus warneri ISK-1 encoding the biosynthesis of and immunity to the lantibiotic, nukacin ISK-1.","date":"2004","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15322349","citation_count":30,"is_preprint":false},{"pmid":"21231794","id":"PMC_21231794","title":"Inhibition of the heterotetrameric K+ channel KCNQ1/KCNE1 by the AMP-activated protein kinase.","date":"2011","source":"Molecular membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/21231794","citation_count":30,"is_preprint":false},{"pmid":"15389592","id":"PMC_15389592","title":"KCNQ1/KCNE1 channels during germ-cell differentiation in the rat: expression associated with testis pathologies.","date":"2005","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15389592","citation_count":30,"is_preprint":false},{"pmid":"11003695","id":"PMC_11003695","title":"A new spontaneous mouse mutation in the Kcne1 gene.","date":"2000","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/11003695","citation_count":30,"is_preprint":false},{"pmid":"9070461","id":"PMC_9070461","title":"cAMP increases apical IsK channel current and K+ secretion in vestibular dark cells.","date":"1997","source":"The Journal of membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/9070461","citation_count":30,"is_preprint":false},{"pmid":"22250012","id":"PMC_22250012","title":"Characterization of KCNQ1 atrial fibrillation mutations reveals distinct dependence on KCNE1.","date":"2012","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/22250012","citation_count":30,"is_preprint":false},{"pmid":"27731317","id":"PMC_27731317","title":"KCNE1 induces fenestration in the Kv7.1/KCNE1 channel complex that allows for highly specific pharmacological targeting.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27731317","citation_count":30,"is_preprint":false},{"pmid":"26418890","id":"PMC_26418890","title":"Probing Structural Dynamics and Topology of the KCNE1 Membrane Protein in Lipid Bilayers via Site-Directed Spin Labeling and Electron Paramagnetic Resonance Spectroscopy.","date":"2015","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26418890","citation_count":30,"is_preprint":false},{"pmid":"8558592","id":"PMC_8558592","title":"Hypo-osmotic challenge stimulates transepithelial K+ secretion and activates apical IsK channel in vestibular dark cells.","date":"1995","source":"The Journal of membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/8558592","citation_count":30,"is_preprint":false},{"pmid":"21296569","id":"PMC_21296569","title":"Working model for the structural basis for KCNE1 modulation of the KCNQ1 potassium channel.","date":"2011","source":"Current opinion in structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/21296569","citation_count":29,"is_preprint":false},{"pmid":"9609707","id":"PMC_9609707","title":"Conformation and ion-channeling activity of a 27-residue peptide modeled on the single-transmembrane segment of the IsK (minK) protein.","date":"1998","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9609707","citation_count":29,"is_preprint":false},{"pmid":"21676880","id":"PMC_21676880","title":"Post-translational N-glycosylation of type I transmembrane KCNE1 peptides: implications for membrane protein biogenesis and disease.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21676880","citation_count":29,"is_preprint":false},{"pmid":"38816749","id":"PMC_38816749","title":"High-throughput functional mapping of variants in an arrhythmia gene, KCNE1, reveals novel biology.","date":"2024","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38816749","citation_count":28,"is_preprint":false},{"pmid":"17951378","id":"PMC_17951378","title":"Cooperative transport between NukFEG and NukH in immunity against the lantibiotic nukacin ISK-1 produced by Staphylococcus warneri ISK-1.","date":"2007","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/17951378","citation_count":28,"is_preprint":false},{"pmid":"8146016","id":"PMC_8146016","title":"Species variants of the IsK protein: differences in kinetics, voltage dependence, and La3+ block of the currents expressed in Xenopus oocytes.","date":"1994","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/8146016","citation_count":28,"is_preprint":false},{"pmid":"22908235","id":"PMC_22908235","title":"KCNQ1 channels do not undergo concerted but sequential gating transitions in both the absence and the presence of KCNE1 protein.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22908235","citation_count":28,"is_preprint":false},{"pmid":"14499862","id":"PMC_14499862","title":"Characterization of a novel Long QT syndrome mutation G52R-KCNE1 in a Chinese family.","date":"2003","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/14499862","citation_count":28,"is_preprint":false},{"pmid":"33373586","id":"PMC_33373586","title":"KCNE1 is an auxiliary subunit of two distinct ion channel superfamilies.","date":"2020","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33373586","citation_count":27,"is_preprint":false},{"pmid":"12962276","id":"PMC_12962276","title":"Swelling-activated chloride and potassium conductance in primary cultures of mouse proximal tubules. Implication of KCNE1 protein.","date":"2003","source":"The Journal of membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/12962276","citation_count":27,"is_preprint":false},{"pmid":"21943417","id":"PMC_21943417","title":"KCNE1 and KCNE2 provide a checkpoint governing voltage-gated potassium channel α-subunit composition.","date":"2011","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/21943417","citation_count":25,"is_preprint":false},{"pmid":"19481127","id":"PMC_19481127","title":"Mapping and identification of the region and secondary structure required for the maturation of the nukacin ISK-1 prepeptide.","date":"2009","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/19481127","citation_count":25,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51681,"output_tokens":9107,"usd":0.145824,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18978,"output_tokens":8489,"usd":0.153558,"stage2_stop_reason":"end_turn"},"total_usd":0.299382,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"KCNE1 (minK/IsK) coassembles with KCNQ1 (KvLQT1) to form the cardiac slow delayed-rectifier potassium channel (I(Ks)). Coexpression of the two subunits in heterologous systems produced a current nearly identical to native cardiac I(Ks), establishing KCNE1 as an obligate beta-subunit of this channel complex.\",\n      \"method\": \"Heterologous coexpression in Xenopus oocytes; electrophysiology\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution of native current by coexpression, foundational result independently replicated across many subsequent labs\",\n      \"pmids\": [\"8900283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"KCNE1 (IsK) knockout mice lack potassium secretion into endolymph by strial marginal cells and vestibular dark cells, demonstrating that IsK is required for transepithelial K+ secretion in the inner ear.\",\n      \"method\": \"IsK gene knockout mouse; in vitro short-circuit current measurement of inner ear epithelia\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with specific epithelial transport phenotype, replicated in subsequent knockout studies\",\n      \"pmids\": [\"8982171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The 63-amino-acid sequence covering the transmembrane domain of ISK is sufficient for K+ channel activity. The cytoplasmic region immediately C-terminal to the transmembrane domain is critical for channel activity, while amino-terminal substitutions had little effect. Specific transmembrane residues (e.g., L52I) alter gating properties, supporting ISK as an integral part of the channel pore.\",\n      \"method\": \"Site-directed mutagenesis, deletion/truncation analysis, Xenopus oocyte expression, electrophysiology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with electrophysiological readout, multiple constructs tested in single rigorous study\",\n      \"pmids\": [\"1939241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"IsK protein expression in Xenopus oocytes induces not only a slow K+ current but also a Cl-selective current. Mutagenesis identified distinct N-terminal and C-terminal domains as critical for Cl- and K+ channel activities respectively, supporting a model in which IsK acts as a regulatory activator of distinct endogenous channel complexes.\",\n      \"method\": \"Site-directed mutagenesis; Xenopus oocyte electrophysiology\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — mutagenesis with functional readout in single study; Cl- channel identity not fully resolved in this paper\",\n      \"pmids\": [\"8413671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The three-dimensional NMR structure of KCNE1 shows a curved alpha-helical transmembrane domain flanked by extracellular and intracellular helices. Experimentally restrained docking suggests KCNE1 slows KCNQ1 activation by interacting with the S4-S5 linker in the closed state and binds a gain-of-function cleft in the open state to increase conductance and stabilize the open state.\",\n      \"method\": \"Solution NMR structure determination; computational docking to KCNQ1 models; functional validation\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with experimentally restrained docking and functional correlation; confirmed in lipid bilayer environment by subsequent EPR studies\",\n      \"pmids\": [\"18611041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The stoichiometry of the KCNQ1-KCNE1 complex is flexible, with up to four KCNE1 subunits associating with the four KCNQ1 subunits (up to 4:4). Both voltage-dependence and gating kinetics depend on the relative expression densities of KCNQ1 and KCNE1, suggesting heart rhythm can be regulated by KCNE1 expression level and resulting stoichiometry.\",\n      \"method\": \"Single-molecule fluorescence subunit counting (bleaching); electrophysiology at varied KCNQ1:KCNE1 expression ratios\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-molecule counting is a rigorous quantitative method; functional correlate measured simultaneously; confirmed by subsequent studies\",\n      \"pmids\": [\"20962273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Four LQT5 KCNE1 mutants show distinct cellular phenotypes: V47F and W87R traffic to the cell surface with altered IKs gating; L51H is retained intracellularly and fails to interact functionally with KvLQT1 or HERG; D76N suppresses both IKs and IKr. This establishes KCNE1 as a co-factor for both IKs and IKr channel function.\",\n      \"method\": \"Electrophysiology in Xenopus oocytes and HEK293 cells; immunocytochemistry for surface expression\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary methods (electrophysiology + immunocytochemistry), multiple mutants with distinct phenotypes in two expression systems\",\n      \"pmids\": [\"10400998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KCNQ1/KCNE1 channel complex undergoes RAB5-dependent endocytosis and RAB11-dependent exocytosis/recycling to the plasma membrane. Serum- and glucocorticoid-inducible kinase 1 (SGK1) enhances exocytosis via phosphorylation of phosphoinositide 3-phosphate 5-kinase and generation of PI(3,5)P2, providing a mechanism for stress-induced acceleration of cardiac repolarization.\",\n      \"method\": \"Dominant-negative Rab GTPase constructs; pharmacological inhibition; biochemical trafficking assays; electrophysiology\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (dominant-negative GTPases, kinase pathway dissection, functional readout) in single study\",\n      \"pmids\": [\"17293474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PIP2 directly regulates the KCNQ1-KCNE1 complex; three LQT-associated KCNQ1 mutations (R243H, R539W, R555C) reduce PIP2 affinity of the channel, and direct PIP2 application or restoration of positive charge rescues channel activity, establishing impaired PIP2 interaction as a molecular mechanism for these LQT mutations.\",\n      \"method\": \"Giant excised patch electrophysiology; direct PIP2 application; MTSET chemical rescue; soluble PIP2 analog binding assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal biochemical and electrophysiological methods in single study, including chemical rescue confirming mechanistic model\",\n      \"pmids\": [\"15746441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"cAMP regulation of the KvLQT1/IsK (IKs) complex requires anchoring of protein kinase A (PKA) to the channel complex via A-kinase anchoring proteins (AKAPs). Coexpression of AKAP79, mAKAP fragment, or AKAP15/18 restored cAMP-dependent upregulation of IKs in heterologous cells; Ht31 peptide (disruptor of PKA anchoring) prevented the effect.\",\n      \"method\": \"Whole-cell patch clamp in mammalian heterologous expression systems; AKAP coexpression; Ht31 peptide disruption\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional epistasis with AKAP coexpression and dominant-negative disruption; multiple AKAP constructs tested\",\n      \"pmids\": [\"11299204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"KCNE1 requires co-assembly with specific K+ channel alpha-subunits for efficient trafficking and cell surface expression; without co-assembly, KCNE1 is retained in the early secretory pathway. Co-assembly mediates progression through the secretory pathway.\",\n      \"method\": \"Enzymatic deglycosylation; immunofluorescence; quantitative cell-surface labeling in multiple cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in multiple cell lines; mechanistic trafficking conclusion supported by complementary approaches\",\n      \"pmids\": [\"17065152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Protein kinase C (PKC) activation downregulates IKs by stimulating dynamin-dependent endocytosis of KCNQ1-KCNE1 complexes. The effect requires phosphorylation of KCNE1 at serine 102; the KCNE1-S102A mutation abolishes PKC-induced endocytosis and current reduction. This mechanism was confirmed in neonatal mouse ventricular myocytes.\",\n      \"method\": \"Patch clamping; fluorescence microscopy with transferrin endosome colocalization; dominant-negative dynamin (K44A); site-directed mutagenesis (S102A); neonatal mouse myocytes\",\n      \"journal\": \"Heart rhythm\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, dominant-negative approach, phospho-null mutation, and native cardiomyocyte confirmation\",\n      \"pmids\": [\"21699843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KCNE1 and KCNE2 undergo sequential proteolytic cleavage: first by either alpha-secretase or BACE1, then by presenilin/gamma-secretase, generating C-terminal fragments and intracellular domains. Elevated BACE1 activity increases KCNE1 processing and shifts the KCNE1/KCNQ1 channel activation curve to more positive potentials, decreasing cardiac repolarization efficiency.\",\n      \"method\": \"Biochemical CTF detection in HEK293T, B104 neuroblastoma cells, cardiomyocytes, and primary neurons; secretase inhibitors; BACE1 overexpression; electrophysiology\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell types, pharmacological and genetic manipulation of secretases, functional electrophysiological readout in same study\",\n      \"pmids\": [\"23504710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The KCNE1 C-terminal cytoplasmic domain forms a protein-protein interaction with the KCNQ1 S6 activation gate and S4-S5 linker. Cysteine cross-linking identified three KCNQ1 residues (H363C, P369C, I257C) that form disulfide bonds with KCNE1 C-terminal cysteine residues; these interactions are state-dependent (primarily in closed state) and slow activation gate opening.\",\n      \"method\": \"Cysteine cross-linking (disulfide bond formation); electrophysiology; biochemical screening of >300 cysteine pairs\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic cysteine cross-linking with state-dependent functional validation; large-scale screening with statistical analysis\",\n      \"pmids\": [\"20479109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KCNE1 divides voltage sensor (S4) movement in KCNQ1/KCNE1 channels into two steps: first, independent movement of each S4 (generating main gating charge, underlying activation delay); second, a slower concerted conformational change of all four voltage sensors and the gate that opens the channel. KCNE1 thus mechanistically uncouples these two steps with different voltage dependences.\",\n      \"method\": \"Voltage clamp fluorometry; S4 mutagenesis; pharmacological isolation of gating steps\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — voltage clamp fluorometry directly reports voltage sensor movement independently of current; mutagenesis and pharmacology used orthogonally\",\n      \"pmids\": [\"24769622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LQT mutations at the KCNQ1 helix C / KCNE1 distal C-terminus intracellular interface disrupt KCNQ1-KCNE1 subunit interaction. KCNQ1 helix C mutations impair PIP2 modulation (decreased current density and depolarizing activation shift), while KCNE1 C-terminus mutation P127T suppresses yotiao-dependent cAMP/PKA upregulation of IKs by reducing KCNQ1 S27 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation; electrophysiology; mutagenesis; PKA phosphorylation assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, multiple mutations, PKA phosphorylation biochemistry, electrophysiological phenotyping in single study\",\n      \"pmids\": [\"25037568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KCNE1 affects both the first S4 movement and the gate of KCNQ1, whereas KCNE3 primarily affects S4 movement and only affects the gate if S4-to-gate coupling is intact. A triple mutation in the KCNE3 transmembrane segment middle region introduced KCNE1-like effects on S4 movement and gating, mapping the functional divergence of KCNE1 and KCNE3 to specific transmembrane residues.\",\n      \"method\": \"Voltage clamp fluorometry; S4 mutagenesis; PIP2 depletion to separate S4 movement from gate opening\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — voltage clamp fluorometry directly measures voltage sensor movements; orthogonal genetic and pharmacological perturbations in single rigorous study\",\n      \"pmids\": [\"28808020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"KCNE1 (IsK) protein localizes specifically to the endolymphatic (apical/luminal) surface of strial marginal cells in the cochlea, as determined by immunohistochemistry with two distinct antibodies, suggesting a direct role in K+ permeation at the luminal membrane.\",\n      \"method\": \"Immunohistochemistry with two antibodies targeting distinct epitopes of the Isk protein\",\n      \"journal\": \"Hearing research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization by immunohistochemistry with two independent antibodies; functional consequence inferred from location\",\n      \"pmids\": [\"1663105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The IsK protein modulates both pharmacological sensitivity and activator responses of the IKs channel: IKs blockers (293B, azimilide, 17β-estradiol) have 6–100-fold higher affinity for KvLQT1/IsK heteromers than KvLQT1 alone. IKs activators (mefenamic acid, DIDS) dramatically enhance heteromeric IKs by arresting channels in an open state, but have little effect on KvLQT1 homomers, demonstrating a direct IsK-dependent pharmacological mechanism.\",\n      \"method\": \"Heterologous coexpression in Xenopus oocytes; electrophysiology; pharmacological profiling\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct pharmacological comparison of homomeric vs. heteromeric channels; multiple drug classes tested\",\n      \"pmids\": [\"9313924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"IsK/KCNE1 knockout mice exhibit a steeper QT-RR relationship and longer QT intervals at slow heart rates, indicating that the isk gene product blunts QT adaptation to heart rate variations. The absence of IKs leads to a paradoxically shorter QT at fast rates, revealing the channel's role in rate-dependent repolarization reserve.\",\n      \"method\": \"ECG recordings in isk-/- mice; comparison with wild-type; cellular electrophysiology\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with in vivo electrocardiographic phenotype; functionally informative at both whole-animal and cellular levels; replicated in separate knockout lines\",\n      \"pmids\": [\"9670922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KCNE1-null mice spontaneously develop atrial fibrillation associated with shortened atrial action potentials and increased outward K+ currents (including KCNQ1-sensitive currents) in atrial myocytes. At rapid pacing rates, IKs (KCNQ1+KCNE1) does not accumulate due to sigmoidal activation, whereas KCNQ1 alone accumulates markedly, explaining the paradoxical increase in outward current with KCNE1 deletion.\",\n      \"method\": \"KCNE1-null mouse model; in vivo ECG; patch clamp of atrial myocytes; isoproterenol and vagomimetic pharmacology; CHO cell electrophysiology\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic model with in vivo arrhythmia phenotype and mechanistic dissection by patch clamp and pharmacology\",\n      \"pmids\": [\"15947250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Stilbene and fenamate IKs activators bind to an extracellular domain flanking the IsK transmembrane segment and rescue dominant-negative loss-of-function in IsK C-terminal mutants, including the naturally occurring LQT5 mutant D76N, by restoring slow activation gating. This reveals allosteric interactions between extracellular/intracellular boundaries of the IsK transmembrane segment and between alpha and beta subunit domains.\",\n      \"method\": \"Mutagenesis; Xenopus oocyte electrophysiology; pharmacological rescue with stilbenes and fenamates\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological rescue of specific mutants with mutagenesis, identifying binding domain; single lab\",\n      \"pmids\": [\"10428953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SGK1, SGK2, SGK3, and protein kinase B (PKB) all stimulate KCNE1/KCNQ1 channel activity in Xenopus oocytes; kinase-dead SGK1 (K127N) had no effect. The stimulation is independent of Na+/K+-ATPase, establishing serum/glucocorticoid-inducible kinases as direct upstream regulators of KCNE1-dependent K+ channel activity.\",\n      \"method\": \"Xenopus oocyte two-electrode voltage clamp; coexpression of wild-type, constitutively active, and kinase-dead SGK isoforms\",\n      \"journal\": \"Pflugers Archiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead negative control confirms kinase-dependent mechanism; multiple kinase isoforms tested\",\n      \"pmids\": [\"12634932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"AMP-activated protein kinase (AMPK) reduces KCNQ1/KCNE1-mediated currents and decreases KCNQ1 plasma membrane abundance, likely via the ubiquitin ligase Nedd4-2. Nedd4-2 mimicked AMPK's effect. This establishes AMPK as a negative regulator of IKs channel surface expression.\",\n      \"method\": \"Xenopus oocyte voltage clamp; constitutively active and wild-type AMPK coexpression; Nedd4-2 coexpression; immunostaining and confocal imaging of KCNQ1 membrane abundance\",\n      \"journal\": \"Molecular membrane biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional and imaging endpoints; constitutively active kinase construct; Nedd4-2 epistasis tested; single lab\",\n      \"pmids\": [\"21231794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KCNE1 disrupts electrostatic interactions of the C-terminal half of KCNQ1 S4 (S4-C) with the lower conserved glutamate in S2 (Glu170), altering packing around S4 and thereby affecting voltage-dependent gating. Tryptophan scanning of S4 revealed a cluster of S4-C residues where mutations abolish current in the presence of KCNE1.\",\n      \"method\": \"S4 tryptophan scanning mutagenesis; cysteine accessibility and MTS modification; electrophysiology in presence/absence of KCNE1\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with functional readout; KCNE1-dependent effects specifically mapped to S4-C residues; single lab\",\n      \"pmids\": [\"21112284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ERG1 (KCNH2) coimmunoprecipitates with KCNE1 in horse heart tissue, providing direct biochemical evidence for KCNE1 association with the HERG channel complex in native cardiac tissue.\",\n      \"method\": \"Co-immunoprecipitation from native horse heart tissue; immunoblotting; RT-PCR\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP from native tissue with multiple confirmatory methods; single species/lab\",\n      \"pmids\": [\"12063283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The KCNE1 C-terminus interacts with KCNQ1 to regulate channel assembly, open-state stability, and deactivation kinetics. The LQT5 mutant D76N and full C-terminal truncation (Δ70) both shift voltage dependence, decrease current density, accelerate deactivation, and impair rate-dependent IKs facilitation. C-terminal truncation reduces apparent KCNE1 affinity for KCNQ1, impairing surface delivery of the complex.\",\n      \"method\": \"Electrophysiology; co-immunoprecipitation; surface expression assays; overexpression titration in heterologous cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional and biochemical methods; two distinct C-terminal mutations with convergent and divergent phenotypes analyzed\",\n      \"pmids\": [\"19340287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KCNE1 constrains the Kv7.1 voltage sensor by lodging at the inter-VSD S4-S1 interface between adjacent subunits, as revealed by tryptophan scanning mutagenesis of S4 and cysteine engineering. Specific S4 perturbations that mimic KCNE1 effects or compromise KCNE1 regulation mapped to this interface.\",\n      \"method\": \"Tryptophan-scanning mutagenesis of KCNQ1 S4; cysteine engineering; electrophysiology with and without KCNE1\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic S4 tryptophan scan with functional readout; inter-VSD interface localized by double-mutant analysis; single lab\",\n      \"pmids\": [\"18398469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Post-translational N-glycosylation of KCNE1 occurs at two sites: one co-translational and one post-translational. Ablation of the co-translational glycosylation site also prevents post-translational glycosylation, resulting in unglycosylated KCNE1 that cannot reach the cell surface with its cognate K+ channel. Engineering the post-translational site into a co-translational context restored monoglycosylation and anterograde trafficking.\",\n      \"method\": \"Site-directed mutagenesis of glycosylation sites; pulse-chase glycosylation kinetics; cell surface expression assays; mutagenic site conversion\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mechanistic mutagenesis with kinetic glycosylation assays and site conversion rescue; rigorous biogenic mechanism established in single study\",\n      \"pmids\": [\"21676880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The transmembrane domain of KCNE1 is helical and slightly curved in proteoliposomes (POPC/POPG bilayers), consistent with the solution NMR structure in micelles. DEER distance measurements in three membrane environments confirmed the curvature is maintained in lipid bilayers, supporting its functional relevance.\",\n      \"method\": \"Double electron-electron resonance (DEER) spectroscopy; simulated annealing MD simulations; comparison across LMPG micelles, proteoliposomes, and lipodisq nanoparticles\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural measurements in physiologically relevant lipid bilayer environment; multiple membrane systems compared orthogonally\",\n      \"pmids\": [\"25234231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KCNE1 association with KCNQ1 creates fenestrations in the channel that are not present in KCNQ1 alone, providing a binding site for adamantane derivative inhibitors (e.g., JNJ303). These compounds access the channel through KCNE1-dependent fenestrations, enabling highly subtype-specific pharmacological targeting.\",\n      \"method\": \"Scanning mutagenesis; electrophysiology; chemical ligand modification; chemical cross-linking; MS/MS analysis; molecular modelling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods including cross-linking with MS/MS identification of binding site and structural modeling; mechanistically validated\",\n      \"pmids\": [\"27731317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KCNE1 fulfils criteria of a bona fide auxiliary subunit of the TMEM16A chloride channel (anoctamin superfamily), in addition to its established role with KCNQ1. KCNE1 assembly with TMEM16A switches channel behavior from calcium-dependent to voltage-dependent. Clinically relevant KCNE1 mutations within the TMEM16A-regulating domain abolish TMEM16A modulation.\",\n      \"method\": \"Pharmacology; gene invalidation (knockout); single-molecule fluorescence co-assembly assays; electrophysiology with KCNE1 mutants\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including single-molecule fluorescence and gene knockout; clinically relevant mutants tested; novel channel partnership established\",\n      \"pmids\": [\"33373586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KCNQ1 residue V141 (in S1) is in direct physical proximity to KCNE1 as shown by disulfide cross-linking: V141C forms disulfide bonds with cysteine-substituted KCNE1 residues, while adjacent S140C does not. This structural difference explains the differential KCNE1 dependence of two familial atrial fibrillation mutations (V141M vs. S140G) and maps the KCNE1-KCNQ1 S1 interaction interface.\",\n      \"method\": \"Disulfide cross-linking; electrophysiology; KCNE1-dependence analysis in Xenopus oocytes\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cross-linking directly establishes proximity; functional correlation to KCNE1 dependence; single lab\",\n      \"pmids\": [\"22250012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Saturation mutagenesis variant effect mapping of all KCNE1 single-amino-acid variants revealed that most functionally deleterious variants affect channel gating rather than surface trafficking. Residues at positions 56-104 are dispensable for trafficking but essential for function. 73% of residues highly intolerant to variation are predicted to contact KCNQ1 or calmodulin, identifying these interfaces as critical for KCNE1 function.\",\n      \"method\": \"Saturation mutagenesis coupled with high-throughput sequencing (variant effect mapping); cell surface expression assay; functional IKs assay; validated against gold-standard electrophysiology\",\n      \"journal\": \"Genome medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — comprehensive mutagenesis of 2554+ variants with two independent functional readouts; validated against electrophysiology gold standard\",\n      \"pmids\": [\"38816749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Protein kinase C (PKC) enhancement or inhibition of IsK channel current is determined by specific cytoplasmic residues. Guinea pig IsK (with serine at position 102 context) shows PKC-enhanced current amplitude mimicking native IKs; mutagenesis of four cytoplasmic amino acids converts the PKC response from enhancement to inhibition, mapping the PKC regulatory site to the intracellular C-terminal domain.\",\n      \"method\": \"Mutagenesis; Xenopus oocyte electrophysiology; phorbol ester activation of PKC\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis identifies specific cytoplasmic residues; functional phenotype reversal confirms mechanism; single lab\",\n      \"pmids\": [\"7510407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"KCNE1 (IsK) and KCNQ1 (KvLQT1) co-localize at the apical membrane of vestibular dark cells in a polarized fashion, as demonstrated by immunocytochemistry in wild-type and kcne1-/- mice. KCNE1-null mice develop progressive vestibular epithelial degeneration and endolymphatic space collapse, establishing KCNE1 as required for dark-cell endolymph homeostasis.\",\n      \"method\": \"In situ hybridization; RT-PCR; immunocytochemistry; ultrastructural analysis of kcne1-/- mice\",\n      \"journal\": \"Hearing research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple imaging modalities; genetic knockout phenotype; co-localization confirmed at cellular level; replicated across multiple inner ear studies\",\n      \"pmids\": [\"11223304\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KCNE1 (minK/IsK) is a single-transmembrane beta-subunit that obligatorily coassembles with KCNQ1 to form the cardiac slow delayed-rectifier IKs channel complex, with variable stoichiometry (up to 4:4); KCNE1 slows KCNQ1 activation by restraining S4 voltage-sensor movement in two sequential steps and interacting with the S4-S5 linker and S6 gate, enhances conductance by stabilizing the open state via a gain-of-function cleft, and is regulated post-translationally by N-glycosylation, PKA (anchored via AKAPs/yotiao), PKC (phospho-S102 triggering dynamin-dependent endocytosis), SGK, AMPK (via Nedd4-2), PIP2, and BACE1/gamma-secretase cleavage; in the inner ear KCNE1 localizes apically on strial marginal cells and vestibular dark cells where it is essential for K+ secretion into endolymph; KCNE1 also functions as an auxiliary subunit of TMEM16A chloride channels, switching them from calcium-dependent to voltage-dependent gating.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KCNE1 (minK/IsK) is a single-transmembrane auxiliary β-subunit that obligatorily coassembles with the KCNQ1 (KvLQT1) α-subunit to reconstitute the cardiac slow delayed-rectifier potassium current IKs [#0]. Its short transmembrane domain, with the immediately C-terminal cytoplasmic region, is sufficient and necessary for channel activity, and KCNE1 behaves as an integral component of the channel that sets gating rather than a passive accessory [#2]; its transmembrane helix adopts a curved conformation maintained in lipid bilayers [#4, #29]. KCNE1 slows KCNQ1 activation through defined structural contacts: it lodges at the inter-voltage-sensor S4-S1 interface and disrupts S4-C/S2 electrostatic packing to restrain voltage-sensor movement [#27, #24], its C-terminus engages the S6 activation gate and S4-S5 linker via state-dependent (closed-state) interactions that slow gate opening [#13], and it splits S4 motion into an initial independent step and a slower concerted gating step, thereby uncoupling charge movement from pore opening [#14, #16]. Up to four KCNE1 subunits associate with the four KCNQ1 subunits, and gating and voltage dependence scale with the KCNQ1:KCNE1 ratio, allowing stoichiometry to tune repolarization [#5]. The channel is further controlled by PIP2 [#8] and by an extensive regulatory network acting on trafficking and gating: AKAP/yotiao-anchored PKA upregulation [#9, #15], PKC-driven endocytosis requiring KCNE1 phosphorylation at Ser102 [#11, #34], SGK/PKB stimulation [#22], AMPK/Nedd4-2-dependent surface downregulation [#23], Rab5/Rab11 endocytic recycling [#7], obligate co-assembly-dependent secretory trafficking [#10], two-site N-glycosylation [#28], and sequential BACE1/γ-secretase cleavage [#12]. KCNE1 also serves as a cofactor for the HERG/IKr (KCNH2) channel [#6, #25] and as a bona fide auxiliary subunit of the TMEM16A chloride channel, switching it from calcium-dependent to voltage-dependent gating [#31]. Beyond the heart, KCNE1 localizes to the apical membrane of strial marginal and vestibular dark cells where it is required for transepithelial K+ secretion and endolymph homeostasis [#1, #17, #35], and KCNE1 variants cause the LQT5 long-QT syndrome through gating, trafficking, and subunit-interface defects [#6, #33].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established that the minimal IsK transmembrane domain and the adjacent cytoplasmic region are sufficient and necessary for K+ channel activity, framing IsK as an integral pore-shaping element rather than a passive accessory.\",\n      \"evidence\": \"Truncation and site-directed mutagenesis with Xenopus oocyte electrophysiology\",\n      \"pmids\": [\"1939241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the partner α-subunit not yet known\", \"No structural basis for gating effects\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Localized IsK protein to the apical/endolymphatic surface of cochlear strial marginal cells, first connecting the protein to inner-ear K+ handling.\",\n      \"evidence\": \"Immunohistochemistry with two distinct anti-IsK antibodies\",\n      \"pmids\": [\"1663105\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role inferred from location only\", \"No genetic loss-of-function evidence yet\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Reported that IsK expression induces a Cl-selective current alongside K+ current, with separable N- and C-terminal determinants, raising the model of IsK as a regulator of distinct endogenous channels.\",\n      \"evidence\": \"Site-directed mutagenesis and Xenopus oocyte electrophysiology\",\n      \"pmids\": [\"8413671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the Cl- channel not resolved\", \"Endogenous oocyte channel contribution unclear\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identified the obligate α-subunit partner: coexpression of KCNE1 with KCNQ1 reconstitutes native cardiac IKs, defining the molecular composition of the slow delayed rectifier.\",\n      \"evidence\": \"Heterologous coexpression in Xenopus oocytes with electrophysiology\",\n      \"pmids\": [\"8900283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the complex unknown\", \"Mechanism of activation slowing not defined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrated genetically that IsK is required for transepithelial K+ secretion into endolymph, establishing its physiological role in inner-ear epithelia.\",\n      \"evidence\": \"IsK knockout mouse with short-circuit current measurement of inner-ear epithelia\",\n      \"pmids\": [\"8982171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the secretory channel partner in vivo not addressed here\", \"Cardiac consequences not measured in same study\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed in vivo that IsK blunts QT adaptation to heart rate, defining IKs as a contributor to rate-dependent repolarization reserve.\",\n      \"evidence\": \"ECG and cellular electrophysiology in isk-/- mice\",\n      \"pmids\": [\"9670922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atrial versus ventricular contribution not separated\", \"Molecular basis of rate dependence not yet mechanistic\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Mapped the PKC regulatory response of IsK to specific cytoplasmic C-terminal residues, showing intracellular determinants set whether PKC enhances or inhibits current.\",\n      \"evidence\": \"Mutagenesis and phorbol-ester PKC activation in Xenopus oocytes\",\n      \"pmids\": [\"7510407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphorylation site not pinpointed in this study\", \"Native cardiomyocyte relevance not tested\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrated that IsK confers distinct pharmacological sensitivity on the IKs heteromer, showing blockers and activators act through an IsK-dependent mechanism on the open state.\",\n      \"evidence\": \"Pharmacological profiling of homomeric vs heteromeric channels in Xenopus oocytes\",\n      \"pmids\": [\"9313924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Drug binding site not localized\", \"Single expression system\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined KCNE1 as a co-factor for both IKs and IKr by characterizing LQT5 mutants with divergent trafficking and gating defects.\",\n      \"evidence\": \"Electrophysiology and surface immunocytochemistry of LQT5 mutants in oocytes and HEK293\",\n      \"pmids\": [\"10400998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Native IKr association not yet shown biochemically\", \"Structural interface with HERG undefined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Localized stilbene/fenamate activator binding to an extracellular domain flanking the IsK transmembrane segment and showed pharmacological rescue of LQT5 mutants, revealing allosteric α-β coupling.\",\n      \"evidence\": \"Mutagenesis and pharmacological rescue in Xenopus oocytes\",\n      \"pmids\": [\"10428953\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Precise binding residues not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that cAMP/PKA upregulation of IKs requires PKA anchoring to the channel via AKAPs, linking adrenergic signaling to the complex.\",\n      \"evidence\": \"AKAP coexpression and Ht31 disruption with whole-cell patch clamp\",\n      \"pmids\": [\"11299204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation target residue not mapped here\", \"Native cardiomyocyte AKAP identity not defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Provided biochemical evidence in native cardiac tissue that KCNE1 associates with ERG1/HERG, supporting a physical KCNE1-IKr partnership in vivo.\",\n      \"evidence\": \"Co-immunoprecipitation and RT-PCR from horse heart tissue\",\n      \"pmids\": [\"12063283\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single species and lab\", \"Functional stoichiometry of KCNE1-HERG not defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated KCNQ1/KCNE1 co-localization at vestibular dark-cell apical membranes and that KCNE1 loss causes epithelial degeneration and endolymphatic collapse.\",\n      \"evidence\": \"In situ hybridization, immunocytochemistry, and ultrastructure of kcne1-/- mice\",\n      \"pmids\": [\"11223304\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degeneration mechanism downstream of K+ secretion failure not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified SGK isoforms and PKB as direct upstream stimulators of KCNE1/KCNQ1 activity independent of Na+/K+-ATPase.\",\n      \"evidence\": \"Coexpression of wild-type, constitutively active, and kinase-dead SGK with two-electrode voltage clamp\",\n      \"pmids\": [\"12634932\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct channel phosphorylation vs trafficking mechanism not distinguished here\", \"Single system\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed PIP2 directly regulates the complex and that LQT KCNQ1 mutations act by reducing PIP2 affinity, establishing impaired lipid interaction as a disease mechanism.\",\n      \"evidence\": \"Giant excised patch electrophysiology, direct PIP2 application, MTSET chemical rescue, and PIP2 binding assay\",\n      \"pmids\": [\"15746441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"KCNE1's specific contribution to the PIP2 site not isolated\", \"Structural PIP2 binding site not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Revealed that KCNE1 loss produces atrial fibrillation through paradoxical increases in outward K+ current, explaining how sigmoidal IKs activation prevents accumulation at fast rates.\",\n      \"evidence\": \"KCNE1-null mouse ECG, atrial myocyte patch clamp, and CHO electrophysiology\",\n      \"pmids\": [\"15947250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human atrial relevance not directly tested\", \"Chamber-specific KCNE1 stoichiometry not measured\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that KCNE1 requires co-assembly with α-subunits to exit the early secretory pathway, defining co-assembly-dependent forward trafficking.\",\n      \"evidence\": \"Deglycosylation, immunofluorescence, and quantitative surface labeling in multiple cell lines\",\n      \"pmids\": [\"17065152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ER quality-control machinery retaining unassembled KCNE1 not identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined endocytic recycling of the complex through Rab5/Rab11 and SGK1-driven exocytosis via PI(3,5)P2, providing a mechanism for stress-accelerated repolarization.\",\n      \"evidence\": \"Dominant-negative Rab constructs, pharmacology, biochemical trafficking assays, and electrophysiology\",\n      \"pmids\": [\"17293474\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo cardiac relevance of the recycling pathway not established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Determined the KCNE1 NMR structure and modeled how it contacts the S4-S5 linker in the closed state and a gain-of-function cleft in the open state to slow activation and raise conductance.\",\n      \"evidence\": \"Solution NMR structure with restrained docking to KCNQ1 and functional validation\",\n      \"pmids\": [\"18611041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure solved in micelles, not the full assembled complex\", \"Docking model not directly visualized\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped KCNE1 to the inter-VSD S4-S1 interface between adjacent subunits where it constrains the Kv7.1 voltage sensor.\",\n      \"evidence\": \"Tryptophan-scanning mutagenesis of KCNQ1 S4 and cysteine engineering with electrophysiology\",\n      \"pmids\": [\"18398469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct cross-link to KCNE1 residues not shown here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established the KCNE1 C-terminus as a regulator of assembly, open-state stability, deactivation, and rate-dependent facilitation, with LQT5 D76N and C-terminal truncation impairing affinity and surface delivery.\",\n      \"evidence\": \"Electrophysiology, co-IP, surface expression, and overexpression titration\",\n      \"pmids\": [\"19340287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Atomic-level C-terminal interaction interface not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Quantified flexible up-to-4:4 stoichiometry and showed gating depends on KCNQ1:KCNE1 ratio, indicating expression-level control of repolarization.\",\n      \"evidence\": \"Single-molecule fluorescence subunit counting with ratio-varied electrophysiology\",\n      \"pmids\": [\"20962273\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo stoichiometry in cardiomyocytes not measured\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified state-dependent disulfide contacts between the KCNE1 C-terminus and the KCNQ1 S6 gate and S4-S5 linker, providing a direct structural basis for slowed gate opening.\",\n      \"evidence\": \"Cysteine cross-linking screen of >300 pairs with electrophysiology\",\n      \"pmids\": [\"20479109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of the interaction during gating not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed KCNE1 disrupts S4-C/S2 (Glu170) electrostatic interactions, altering S4 packing to shape voltage-dependent gating.\",\n      \"evidence\": \"S4 tryptophan scanning, cysteine accessibility/MTS modification, and electrophysiology\",\n      \"pmids\": [\"21112284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Effect on individual gating transitions not fully separated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified two-site N-glycosylation of KCNE1, with a co-translational site governing a subsequent post-translational site and overall surface trafficking competence.\",\n      \"evidence\": \"Glycosylation-site mutagenesis, pulse-chase kinetics, surface assays, and site-conversion rescue\",\n      \"pmids\": [\"21676880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of glycosylation state on gating not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined PKC-induced dynamin-dependent endocytosis of the complex requiring KCNE1 Ser102 phosphorylation, confirmed in native cardiomyocytes.\",\n      \"evidence\": \"Patch clamp, transferrin colocalization, dominant-negative dynamin K44A, S102A mutation, neonatal mouse myocytes\",\n      \"pmids\": [\"21699843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream PKC isoform identity not specified\", \"Adult myocyte relevance not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established AMPK as a negative regulator of IKs surface abundance acting through Nedd4-2.\",\n      \"evidence\": \"Constitutively active AMPK and Nedd4-2 coexpression with voltage clamp and confocal imaging in oocytes\",\n      \"pmids\": [\"21231794\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination site not mapped\", \"Single heterologous system\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Pinpointed KCNQ1 S1 residue V141 in direct proximity to KCNE1, explaining differential KCNE1-dependence of familial atrial fibrillation mutations.\",\n      \"evidence\": \"Disulfide cross-linking and KCNE1-dependence analysis in Xenopus oocytes\",\n      \"pmids\": [\"22250012\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Full S1 interaction surface not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed KCNE1 undergoes sequential α/BACE1 then γ-secretase cleavage, with elevated BACE1 shifting channel activation positively and impairing repolarization.\",\n      \"evidence\": \"CTF biochemistry across multiple cell types, secretase inhibitors, BACE1 overexpression, and electrophysiology\",\n      \"pmids\": [\"23504710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological trigger of cleavage in heart not established\", \"Fate/function of released fragments unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated KCNE1 splits S4 movement into an early independent step and a slower concerted gating step, mechanistically uncoupling charge movement from pore opening.\",\n      \"evidence\": \"Voltage clamp fluorometry, S4 mutagenesis, and pharmacological isolation of gating steps\",\n      \"pmids\": [\"24769622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural correlate of the two-step model not visualized\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified an intracellular KCNQ1 helix C / KCNE1 distal C-terminus interface whose mutations disrupt PIP2 modulation and yotiao-dependent PKA upregulation, integrating gating, lipid, and signaling control.\",\n      \"evidence\": \"Co-IP, electrophysiology, mutagenesis, and PKA phosphorylation assays\",\n      \"pmids\": [\"25037568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the helix C interface not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Distinguished KCNE1 from KCNE3 mechanistically, showing KCNE1 affects both the first S4 movement and the gate, and mapped the divergence to specific transmembrane residues.\",\n      \"evidence\": \"Voltage clamp fluorometry, S4 mutagenesis, and PIP2 depletion in Xenopus oocytes\",\n      \"pmids\": [\"28808020\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of transmembrane residue effects not visualized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed KCNE1 assembly creates channel fenestrations absent in KCNQ1 alone, providing an adamantane (JNJ303) binding site and a route to subtype-selective pharmacology.\",\n      \"evidence\": \"Scanning mutagenesis, electrophysiology, chemical cross-linking with MS/MS, and molecular modeling\",\n      \"pmids\": [\"27731317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the fenestration-drug complex not determined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established KCNE1 as a bona fide auxiliary subunit of the TMEM16A chloride channel, switching it from calcium-dependent to voltage-dependent gating, expanding its role beyond K+ channels.\",\n      \"evidence\": \"Pharmacology, gene knockout, single-molecule co-assembly assays, and electrophysiology with KCNE1 mutants\",\n      \"pmids\": [\"33373586\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological tissue context of KCNE1-TMEM16A not defined\", \"Structure of the assembly not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped the functional consequences of all KCNE1 single-amino-acid variants, showing most deleterious variants affect gating rather than trafficking and concentrate at KCNQ1/calmodulin contact interfaces.\",\n      \"evidence\": \"Saturation mutagenesis variant effect mapping with surface and IKs functional readouts validated against electrophysiology\",\n      \"pmids\": [\"38816749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Calmodulin interaction not directly biochemically characterized in this corpus\", \"In vivo penetrance of variants not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KCNE1 stoichiometry, post-translational modification, and partner choice (KCNQ1 vs HERG vs TMEM16A) are coordinated in native tissues to set repolarization and secretion remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of an assembled KCNE1-containing channel complex in the corpus\", \"In vivo stoichiometry and partner partitioning not quantified\", \"Direct KCNE1-calmodulin interaction not biochemically defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4, 14, 31]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [10, 11, 17, 35]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [10, 28]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [7, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 17, 35]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 11, 22]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [7, 10, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 8, 33]}\n    ],\n    \"complexes\": [\n      \"KCNQ1-KCNE1 (IKs) channel\",\n      \"KCNH2/HERG (IKr) channel\",\n      \"TMEM16A chloride channel\"\n    ],\n    \"partners\": [\n      \"KCNQ1\",\n      \"KCNH2\",\n      \"TMEM16A\",\n      \"AKAP9/yotiao\",\n      \"NEDD4-2\",\n      \"SGK1\",\n      \"BACE1\",\n      \"DNM1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}