Affinage

KCNQ1

Potassium voltage-gated channel subfamily KQT member 1 · UniProt P51787

Length
676 aa
Mass
74.7 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNQ1 (KvLQT1/Kv7.1) is a voltage-gated K+ channel α-subunit that, by coassembling with the single-transmembrane β-subunit minK (KCNE1), reconstitutes the cardiac IKs slow delayed rectifier and supports epithelial K+ recycling across multiple organ systems (PMID:8900283, PMID:8900282, PMID:16314573). The α-subunit assembles as a tetramer through a multitiered C-terminal scaffold: a proximal module that constitutively binds one calmodulin per subunit to fold the intracellular domain, and a distal pair of coiled-coils that drive tetramerization and trafficking (PMID:18165683). KCNE subunit identity tunes gating: KCNE1 acts on both S4 voltage-sensor movement and the gate to slow IKs kinetics and remove the channel's intrinsic voltage-dependent inactivation, whereas KCNE3 shifts S4 movement to extreme hyperpolarized potentials through electrostatic contacts with S4 (R228), rendering the channel constitutively conducting (PMID:9675180, PMID:26668384, PMID:28808020); coupling of the voltage sensor to the pore depends on PIP2 because direct S4–S5/S6 protein contacts are weak (PMID:25559286). Channel surface density is dynamically controlled — PKA upregulation requires AKAP anchoring and a β-tubulin/microtubule interaction (PMID:11299204, PMID:18390900), PKC drives dynamin-dependent endocytosis (PMID:21699843), AMPK/Nedd4-2 directs ubiquitination and lysosomal degradation counterbalanced by USP2 deubiquitylation (PMID:21957902, PMID:22024150), and α1-adrenergic signaling triggers clathrin/AP2-dependent internalization (PMID:31491415). KCNQ1 mutations cause cardiac arrhythmia by distinct mechanisms: dominant-negative Romano-Ward LQT1 mutations versus recessive Jervell and Lange-Nielsen mutations that lack dominant-negative suppression (PMID:9323054, PMID:9312006, PMID:9302275), voltage-sensor-domain mutations that destabilize the S0 scaffold and cause mistrafficking and proteasomal degradation (PMID:29532034), and gain-of-function mutations such as S140G that constitutively activate IKs to cause familial atrial fibrillation (PMID:12522251). Beyond the heart, KCNQ1 is essential for inner ear development and gastric epithelial homeostasis and provides the electrochemical driving force for intestinal and renal electrolyte transport (PMID:11120752, PMID:16314573).

Mechanistic history

Synthesis pass · year-by-year structured walk · 33 steps
  1. 1996 High

    Establishing the molecular identity of the cardiac IKs current resolved how two orphan gene products combine into a physiologically central channel.

    Evidence Heterologous coexpression of KvLQT1 and minK in oocytes and mammalian cells with voltage clamp

    PMID:8900282 PMID:8900283

    Open questions at the time
    • Did not define channel stoichiometry
    • Did not localize the subunit interaction interface
  2. 1997 High

    Functional testing of disease mutations distinguished dominant-negative from simple loss-of-function alleles, explaining the dominant versus recessive inheritance of long-QT syndromes.

    Evidence Coexpression of mutant and wild-type subunits in oocytes/COS cells with voltage clamp

    PMID:9302275 PMID:9312006 PMID:9323054

    Open questions at the time
    • Did not establish whether dominant-negative effects act at assembly, trafficking, or gating
    • Did not resolve structural basis of suppression
  3. 1997 Medium

    Single-subunit characterization showed KvLQT1 alone is a functional, cAMP-responsive, drug-sensitive K+ channel, separating intrinsic α-subunit properties from minK modulation.

    Evidence Oocyte expression with voltage clamp, cAMP elevation, and clofilium pharmacology

    PMID:9108097

    Open questions at the time
    • Mechanism of cAMP enhancement not defined
    • Single lab
  4. 1998 Medium

    Identifying an intrinsic non-C-type voltage-dependent inactivation of homomeric channels, removed by minK, clarified how the β-subunit shapes IKs waveform.

    Evidence Oocyte voltage clamp with recovery/deactivation protocols and varied extracellular K+

    PMID:9675180

    Open questions at the time
    • Structural basis of inactivation not defined
    • Single lab
  5. 2000 Medium

    Dissecting which minK domains modulate gating versus association separated physical assembly from functional tuning and explained why MiRP1 cannot substitute.

    Evidence Deletion/chimeric minK constructs with cadmium block and voltage clamp in oocytes

    PMID:10962015

    Open questions at the time
    • Atomic interface between minK and KCNQ1 not resolved
    • Single lab
  6. 2000 High

    Mouse knockout defined non-cardiac requirements for KCNQ1 in inner ear development and gastric epithelial homeostasis, broadening its physiological scope.

    Evidence Kvlqt1 knockout mice with audiology and histochemistry

    PMID:11120752

    Open questions at the time
    • Did not define the molecular transport partners in each epithelium
    • Cell-type-specific contributions unresolved
  7. 2001 High

    Demonstrating that AKAP anchoring of PKA is required for cAMP regulation explained how IKs is upregulated by adrenergic signaling and why heterologous channels lacking AKAPs are cAMP-insensitive.

    Evidence Coexpression with AKAP isoforms and Ht31 anchoring-disruptor peptide, whole-cell patch clamp

    PMID:11299204

    Open questions at the time
    • Did not map the PKA phosphosite-to-gating linkage
    • Stoichiometry of the signaling complex unknown
  8. 2001 Medium

    Surface biotinylation showed that some dominant-negative LQT1 mutants traffic normally yet still suppress IKs, separating trafficking defects from gating/assembly defects.

    Evidence Surface biotinylation, immunofluorescence, and patch clamp in mammalian cells

    PMID:11087258

    Open questions at the time
    • Mechanism of surface-competent dominant-negative suppression unresolved
    • Single lab
  9. 2003 High

    A gain-of-function mutation linking constitutive IKs activation to familial atrial fibrillation established that both increased and decreased KCNQ1 activity cause arrhythmia.

    Evidence Oocyte expression of S140G across KCNE1/KCNE2 backgrounds with voltage clamp

    PMID:12522251

    Open questions at the time
    • In vivo atrial remodeling consequences not assessed
    • KCNE-dependence of the phenotype incompletely defined
  10. 2003 Medium

    Discovery of a direct KvLQT1–HERG interaction with reciprocal current modulation introduced cross-regulation between the two principal repolarizing channels.

    Evidence Reciprocal Co-IP in CHO and native canine tissue, GST pull-down, patch clamp

    PMID:14585842

    Open questions at the time
    • Physiological significance in intact myocardium unresolved
    • Interaction interface not mapped here
  11. 2004 Medium

    Showing that a minK ER-retention mutant traps KCNQ1 in the ER established ER quality control as a route to channel loss in LQT.

    Evidence Co-transfection, voltage clamp, immunofluorescence, glycosylation analysis

    PMID:14761891

    Open questions at the time
    • ER retention machinery not identified
    • Single lab
  12. 2005 High

    Genetic and pharmacological loss of KCNQ1 defined its role in providing the driving force for intestinal/renal Na+ absorption, Cl- secretion, and gastric acid secretion with systemic absorption phenotypes.

    Evidence Knockout mice plus chromanol 293B inhibition with electrophysiology and biochemistry

    PMID:16314573

    Open questions at the time
    • Did not identify the specific KCNE partners in each epithelium
    • Coupling to specific transporters not resolved
  13. 2005 Medium

    FRET evidence that ER-retained mutants directly interact with wild-type subunits provided a trafficking-based mechanism for dominant-negative suppression.

    Evidence GFP fusions, confocal/FRET microscopy, electrophysiology in CHO-K1 and C2C12

    PMID:15935335

    Open questions at the time
    • ER retention factors not identified
    • Single lab
  14. 2006 Medium

    Identifying an N-terminal juxtamembranous ER-exit motif localized a trafficking determinant whose mutation causes ER retention and dominant-negative suppression.

    Evidence N-terminal truncations, COS-7/cardiomyocyte expression, confocal imaging, electrophysiology

    PMID:17053194

    Open questions at the time
    • Coat/receptor recognizing the motif not identified
    • Single lab
  15. 2007 High

    The crystal structure of the C-terminal assembly domain defined the calmodulin-binding folding module and the tandem coiled-coil tetramerization architecture, providing the structural logic for assembly and trafficking.

    Evidence Recombinant C-terminus, 2.0 Å crystal structure, calmodulin binding and LQT-mutant functional studies

    PMID:18165683

    Open questions at the time
    • Full-length channel structure not resolved here
    • How CaM senses Ca2+ to gate the channel not defined
  16. 2008 Medium

    Identifying a β-tubulin/N-terminus interaction required specifically for the PKA response distinguished microtubule-dependent adrenergic upregulation from basal IKs.

    Evidence Yeast two-hybrid, Co-IP in COS-7 and cardiomyocytes, patch clamp with microtubule drugs and PKA stimulation

    PMID:18390900

    Open questions at the time
    • Mechanistic link between microtubules and PKA effect unresolved
    • Single lab
  17. 2008 Medium

    Pulse-chase analysis tied N-terminal LQT1 mutations to accelerated ubiquitin/proteasome degradation and showed KCNE1 stabilizes the protein, linking trafficking motifs to protein turnover.

    Evidence Pulse-chase radiolabeling, ubiquitination assay, proteasome inhibition, Co-IP, siRNA

    PMID:19114714

    Open questions at the time
    • E3 ligase mediating degradation not identified here
    • Role of Derlin-1 negative
  18. 2009 Medium

    Showing KCNE1 depends on KCNQ1 for surface delivery while KCNE2 can independently traffic and dynamically substitute revealed competitive β-subunit exchange shaping native IKs.

    Evidence Pulse-chase, biotinylation, vesicle injection into oocytes, adenoviral KCNE2 in cardiomyocytes, confocal microscopy

    PMID:19372218

    Open questions at the time
    • In vivo KCNE exchange dynamics unresolved
    • Single lab
  19. 2010 Medium

    EGFR-mediated tyrosine phosphorylation of KCNQ1 defined a kinase-driven upregulation distinct from PKA control.

    Evidence Perforated patch clamp, Co-IP, phospho-Western with kinase/phosphatase inhibitors in HEK293

    PMID:20085748

    Open questions at the time
    • Phosphosites not mapped
    • Physiological context unclear
  20. 2010 Medium

    S3-domain LQT1 mutations were shown to cause loss of IKs predominantly through biophysical gating shifts rather than trafficking, refining mutation mechanism categories.

    Evidence Proteinase K surface assay, whole-cell and action-potential clamp in mammalian cells

    PMID:20421371

    Open questions at the time
    • Structural basis of gating shifts not resolved
    • Single lab
  21. 2010 Medium

    Surface plasmon resonance confirmed direct C-terminal binding between KCNQ1 and HERG with bidirectional current cross-regulation, solidifying physical channel–channel coupling.

    Evidence Co-IP, SPR, immunostaining, patch clamp in CHO cells

    PMID:20833965

    Open questions at the time
    • Interaction interface residues not mapped
    • Native significance incompletely resolved
  22. 2011 High

    Defining PKC-triggered, dynamin-dependent endocytosis requiring KCNE1 S102 phosphorylation established acute regulation of channel surface density.

    Evidence Patch clamp, fluorescence microscopy, dominant-negative dynamin, S102A mutant, PMA in CHO cells and mouse cardiomyocytes

    PMID:21699843

    Open questions at the time
    • Endocytic adaptor recognizing the complex not identified here
    • Fate of internalized channels not tracked
  23. 2011 Medium

    Identifying the AMPK/Nedd4-2 ubiquitination–lysosomal degradation pathway, opposed by USP2 deubiquitylation, established a ubiquitin-based set-point for channel surface abundance.

    Evidence Confocal microscopy, AMPK activators, oocyte electrophysiology, MDCK polarization; Co-IP and Western for USP2

    PMID:21957902 PMID:22024150

    Open questions at the time
    • In vivo balance of Nedd4-2/USP2 unresolved
    • Each finding from a single lab
  24. 2012 Medium

    FRET in intact cells and cardiomyocytes confirmed the C-terminal KCNQ1–hERG interaction is dynamically reduced by cAMP, linking the interaction to adrenergic signaling.

    Evidence Acceptor-photobleach FRET in HEK and primary cardiomyocytes with cAMP analog/forskolin

    PMID:23241319

    Open questions at the time
    • Functional consequence of reduced interaction not quantified
    • Single lab
  25. 2015 High

    Voltage clamp fluorometry resolved how KCNE3 shifts S4 movement via specific electrostatic contacts (D54/D55–R228) to make KCNQ1 constitutively conducting, defining the molecular basis of subunit-specific gating modes.

    Evidence Voltage clamp fluorometry, mutagenesis, PIP2 depletion in oocytes

    PMID:26668384

    Open questions at the time
    • Generalization to other KCNE subunits addressed separately
    • Full quaternary arrangement not visualized
  26. 2015 Medium

    Computational and experimental analysis identified PIP2 as the obligatory mediator of voltage-sensor-to-pore coupling, explaining KCNQ1's weak direct S4–S5/S6 electromechanical linkage.

    Evidence Molecular dynamics simulations, electrophysiology, mutagenesis

    PMID:25559286

    Open questions at the time
    • PIP2 binding site not crystallographically confirmed here
    • Single lab
  27. 2015 Medium

    BACE1 was identified as a non-enzymatic β-subunit-like modulator of IKs gating expressed in cardiac myocytes, expanding the channel's accessory partners.

    Evidence Co-IP, FRAP, patch clamp in HEK293T, cardiomyocytes, and BACE1 knockout mice

    PMID:26454161

    Open questions at the time
    • Structural basis of BACE1 modulation unknown
    • Single lab
  28. 2015 Medium

    Linking KCNQ1 to β-catenin/E-cadherin at epithelial junctions revealed a channel-independent role in maintaining epithelial phenotype and restraining Wnt signaling in colorectal cells.

    Evidence shRNA knockdown, overexpression, confocal microscopy, spheroid/invasion assays, chromanol 293B in CRC lines

    PMID:28373572

    Open questions at the time
    • Direct versus indirect β-catenin binding not resolved
    • In vivo tumor relevance not established here
  29. 2017 High

    Comparative voltage clamp fluorometry established that KCNE1 modulates both S4 and the gate while KCNE3 acts mainly on S4, mapping the transmembrane determinants of differential KCNE gating.

    Evidence Voltage clamp fluorometry, mutagenesis, PIP2 depletion in oocytes

    PMID:28808020

    Open questions at the time
    • Atomic-resolution KCNE–KCNQ1 complex not resolved here
    • How S4-to-gate coupling is transmitted not fully defined
  30. 2018 High

    Systematic analysis of 51 VSD variants showed that most loss-of-function VSD mutations destabilize the domain and cause mistrafficking/proteasomal degradation, with the S0 helix acting as the central organizing scaffold.

    Evidence Surface expression, proteasome inhibition, protein stability and functional assays in mammalian cells

    PMID:29532034

    Open questions at the time
    • Structural models of each destabilized variant not provided
    • Chaperone/QC machinery handling VSD mutants not identified
  31. 2019 Medium

    Defining α1-adrenergic-receptor-driven AP2/clathrin internalization via the AMPK/Nedd4-2 pathway, requiring C-terminal PY and YXXΦ motifs, added a receptor-coupled route to surface channel downregulation.

    Evidence HaloTag surface labeling, confocal microscopy, motif mutagenesis in rat neonatal cardiomyocytes

    PMID:31491415

    Open questions at the time
    • In vivo cardiac consequences not assessed
    • Single lab
  32. 2020 Medium

    Demonstrating an unconventional Golgi-bypass secretory route to ER–plasma-membrane junctions where Kv7.1–KCNE1 assemble revised where and how the channel complex is formed.

    Evidence Confocal microscopy, FRAP, biochemical trafficking assays, brefeldin A/Golgi disruption

    PMID:32270035

    Open questions at the time
    • Machinery directing Golgi bypass not identified
    • Single lab
  33. 2020 High

    Agonist antibodies that shift activation and increase open probability provided proof-of-concept that IKs can be pharmacologically enhanced to rescue prolonged repolarization.

    Evidence Purified antibodies, whole-cell and single-channel recordings in CHO IKs cells, action potentials in LQT2 iPSC-cardiomyocytes

    PMID:32354382

    Open questions at the time
    • Antibody binding epitope on the channel not mapped
    • In vivo efficacy not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified atomic-resolution model of how KCNE subunit identity, PIP2, calmodulin, and the C-terminal scaffold jointly set gating mode, and how the full surface-density regulatory network operates in intact myocardium, remains unresolved.
  • No full-length channel–KCNE structure in the corpus
  • Integration of multiple trafficking/degradation pathways in vivo not established
  • Quantitative coupling of accessory partners (HERG, BACE1) to native repolarization unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005886 plasma membrane 4
Pathway
R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-382551 Transport of small molecules 1
Partners
BACE1CALM (CALMODULIN)KCNE1KCNE2KCNE3KCNH2/HERGNEDD4L (NEDD4-2)TUBB (BETA-TUBULIN)
Complex memberships
KCNQ1-KCNE1 (IKs) channel complexKCNQ1-KCNE3 channel complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 KCNQ1 (KvLQT1) coassembles with minK (IsK) to form the cardiac IKs slow delayed rectifier potassium channel; coexpression of the two proteins in Xenopus oocytes and mammalian cells reconstituted a current with biophysical and pharmacological properties nearly identical to native cardiac IKs. Heterologous coexpression in Xenopus oocytes and mammalian cells, two-electrode voltage clamp, whole-cell patch clamp Nature High 8900282 8900283
1997 Most LQT1-associated KvLQT1 mutations (e.g., A177P, T311I, L272F) abolish homomeric channel function and suppress wild-type KvLQT1 and IKs currents by a dominant-negative mechanism when coexpressed with wild-type subunit in Xenopus oocytes. Xenopus oocyte expression, two-electrode voltage clamp, coexpression of mutant and wild-type subunits Circulation High 9302275 9312006 9323054
1997 The Jervell and Lange-Nielsen syndrome (recessive) KvLQT1 mutations abolish channel function without dominant-negative suppression of the wild-type subunit, explaining autosomal recessive inheritance, whereas Romano-Ward (dominant) mutations act via dominant-negative suppression. Heterologous expression in COS cells and Xenopus oocytes, two-electrode voltage clamp, coexpression of mutant and wild-type subunits The EMBO journal / Human molecular genetics High 9302275 9312006
1997 IsK (minK) not only alters the kinetics of KvLQT1 but also changes its ion selectivity when the two subunits are coexpressed. Xenopus oocyte coexpression, two-electrode voltage clamp, ion substitution experiments Human molecular genetics Medium 9302275
1997 KCNQ1 is imprinted in a tissue-specific manner: it shows preferential expression from one parental allele in most somatic tissues but lacks imprinting in cardiac muscle, explaining lack of parent-of-origin effect in LQT syndrome. Allele-specific expression analysis, chromosomal rearrangement mapping in BWS patients Nature genetics Medium 9020845
1997 KvLQT1 channels expressed alone in Xenopus oocytes exhibit a rapidly activating, K+-selective outward current; cAMP elevation nearly doubles KvLQT1 current amplitude, and clofilium (class III antiarrhythmic) substantially inhibits the current. Xenopus oocyte expression, two-electrode voltage clamp, pharmacological agents, cAMP elevation Proceedings of the National Academy of Sciences of the United States of America Medium 9108097
1998 Homomeric KvLQT1 channels undergo intrinsic voltage-dependent inactivation that is independent of extracellular potassium concentration (unlike classical C-type inactivation); coexpression with minK largely removes this inactivation. Xenopus oocyte expression, two-electrode voltage clamp, recovery from inactivation and deactivation protocols, varied extracellular K+ Biophysical journal Medium 9675180
1998 MinK-KvLQT1 fusion protein experiments support multiple stoichiometries of the assembled IKs channel; the uniquely slow kinetics of IKs arise from voltage-dependent conformational changes of the channel protein, not from subunit assembly per se. Fusion protein construction, CHO cell transfection, whole-cell patch clamp The Journal of biological chemistry Medium 9852064
2000 The MinK C-terminus is necessary for gating modulation of KvLQT1 but not for physical association; the MinK transmembrane domain is required together with the C-terminus for full gating modulation; MiRP1 cannot modulate KvLQT1 due to differences within its transmembrane domain. Xenopus oocyte coexpression, deletion and chimeric MinK constructs, cadmium block assay for association, two-electrode voltage clamp The Journal of general physiology Medium 10962015
2000 Targeted disruption of murine Kvlqt1 causes complete deafness with severe anatomic disruption of cochlear and vestibular end organs and gastric mucous neck cell hyperplasia, establishing essential roles for Kvlqt1 in inner ear development and gastric epithelial homeostasis. Gene knockout mice, audiological testing, histochemistry The Journal of clinical investigation High 11120752
2001 AKAP proteins (AKAP79, mAKAP fragment, AKAP15/18) are required to anchor PKA to the KvLQT1/IsK channel complex to reconstitute cAMP regulation of IKs; in their absence, KvLQT1/IsK complexes in heterologous systems are insensitive to cAMP. Heterologous coexpression in mammalian cells, whole-cell patch clamp, PKA anchor disruptor peptide (Ht31) American journal of physiology. Heart and circulatory physiology High 11299204
2001 Several LQT1 KCNQ1 missense mutations (S225L, Y281C, Y315C) traffic to the cell surface but produce dominant-negative suppression of wild-type IKs current; others (A300T) reach the surface but have mild dysfunction without dominant-negative effect. Cell surface biotinylation, immunofluorescence, whole-cell patch clamp in mammalian cells American journal of physiology. Heart and circulatory physiology Medium 11087258
2003 The KCNQ1 S140G gain-of-function mutation causes familial atrial fibrillation by constitutively activating IKs (KCNQ1/KCNE1) and KCNQ1/KCNE2 currents, reducing atrial action potential duration and effective refractory period. Heterologous expression in Xenopus oocytes, two-electrode voltage clamp, functional comparison of wild-type vs. mutant Science High 12522251
2003 KvLQT1 physically interacts with HERG alpha-subunits; coexpression accelerates HERG deactivation and increases HERG current density and membrane expression. HERG and KvLQT1 coimmunoprecipitate in CHO cells and native canine cardiac tissue, and KvLQT1 binds to a C-terminal HERG GST fusion protein. Co-immunoprecipitation in CHO cells and native cardiac tissue, GST pull-down, immunostaining, whole-cell patch clamp The Journal of biological chemistry Medium 14585842
2004 An LQT minK-L51H mutation causes ER retention of minK and reduces surface expression of coexpressed KvLQT1 by sequestering it in the ER; wild-type minK rescues KvLQT1 surface expression, demonstrating that ER quality control can trap KvLQT1/minK complexes. Co-transfection in mammalian cells, whole-cell voltage clamp, immunofluorescence, glycosylation analysis American journal of physiology. Cell physiology Medium 14761891
2005 Pharmacological inhibition and gene knockout of KCNQ1 impairs the driving force for proximal tubular and intestinal Na+ absorption, gastric acid secretion, and cAMP-induced jejunal Cl- secretion; Kcnq1 knockout mice show impaired intestinal absorption, reduced serum vitamin B12, macrocytic anemia, and fecal electrolyte loss. KCNQ1 knockout mice, pharmacological inhibition with chromanol 293B, electrophysiological and biochemical measurements Proceedings of the National Academy of Sciences of the United States of America High 16314573
2005 Several LQT1 KCNQ1 mutations are retained in the endoplasmic reticulum; some exert dominant-negative effects on wild-type KCNQ1 trafficking by direct interaction in the ER, demonstrated by FRET microscopy. GFP-fusion proteins, confocal microscopy, FRET microscopy, electrophysiology in CHO-K1 and C2C12 cells Cardiovascular research Medium 15935335
2006 The N-terminal juxtamembranous region of KCNQ1 (containing residues Y111, L114, P117) is a critical trafficking motif required for ER exit; LQT1 mutations Y111C and L114P cause ER retention and dominant-negative suppression of wild-type KCNQ1 trafficking; this motif is structurally conserved across KCNQ channels. N-terminal truncation mutants, COS-7 cell and cardiomyocyte re-expression, confocal microscopy, electrophysiology Circulation research Medium 17053194
2007 The KCNQ1 C-terminus functions as a multitiered scaffold: its proximal half constitutively binds one calmodulin per subunit, critical for proper folding of the intracellular domain; its distal half directs tetramerization via tandem coiled-coils (a dimeric first coiled-coil that forms a dimer of dimers, and a parallel tetrameric outer coiled-coil), with both coiled-coils cooperating for assembly and trafficking. Recombinant C-terminal domain expression, crystal structure at 2.0 Å resolution, calmodulin binding assay, structure-based and LQT mutant functional studies The Journal of biological chemistry High 18165683
2008 Beta-tubulin directly interacts with the KCNQ1 N-terminus; this interaction is required for the IKs response to PKA-mediated stimulation (but not for basal IKs or osmotic challenge), while PKA phosphorylation of KCNQ1 and Yotiao association are maintained after microtubule disruption. Yeast two-hybrid, co-immunoprecipitation in COS-7 cells and guinea pig cardiomyocytes, immunocytochemistry, patch clamp with microtubule-disrupting/stabilizing agents and PKA stimulation Cardiovascular research Medium 18390900
2008 LQT1-associated N-terminal mutations Y111C, L114P, and P117L cause increased proteasomal degradation of KCNQ1 (shorter half-life) via ubiquitination; KCNE1 stabilizes both wild-type and mutant KCNQ1 protein; Derlin-1 co-immunoprecipitates with KCNQ1 but does not affect KCNQ1 steady-state expression or degradation. Pulse-chase radiolabeling, ubiquitination assay, proteasome inhibitor treatment, co-immunoprecipitation, siRNA knockdown The Journal of biological chemistry Medium 19114714
2009 KCNE1 relies on KCNQ1 coassembly for efficient cell surface expression; KCNE2 can independently traffic to the cell surface and dynamically substitute for KCNE1 in the KCNQ1-KCNE1 complex, with KCNE1 turnover occurring in the complex; KCNE2 overexpression in guinea pig ventricular myocytes reduced native IKs current density. Pulse-chase experiments, biotinylation assay, vesicle injection into KCNQ1-expressing oocytes, adenoviral KCNE2 expression in cardiomyocytes, confocal microscopy The Journal of biological chemistry Medium 19372218
2010 LQT1-causing S3 domain mutations in KCNQ1 (D202H/N, I204F/M, V205M, S209F, V215M) predominantly cause loss of IKs repolarizing current through biophysical effects on channel gating (positive voltage shift of activation, slowed activation, accelerated deactivation), with most mutant channels still reaching the surface; S209F also reduces current density (~75% reduction). Proteinase K surface expression assay, whole-cell patch clamp in mammalian cells, action potential clamp protocols The Journal of general physiology Medium 20421371
2010 KCNQ1 and HERG interact via their C-termini; surface plasmon resonance confirms direct physical association between the two C-terminal domains; pore mutant KvLQT1 reduces HERG surface expression and IKr, while HERG reduces IKs, consistent with bidirectional functional cross-regulation. Co-immunoprecipitation, surface plasmon resonance, immunostaining, stable CHO cell lines with transient transfection, patch clamp American journal of physiology. Heart and circulatory physiology Medium 20833965
2011 PKC activation downregulates IKs by stimulating dynamin-dependent endocytosis of KCNQ1-KCNE1 channel complexes; this requires phosphorylation of KCNE1 serine 102 (S102A abolishes effect) and functional dynamin (K44A-dynamin blocks internalization); the same mechanism operates in neonatal mouse ventricular myocytes. Patch clamp, fluorescence microscopy, dominant-negative dynamin coexpression, S102A mutant, phorbol ester (PMA) treatment in CHO cells and mouse cardiomyocytes Heart rhythm High 21699843
2011 AMPK activation induces Nedd4-2-dependent ubiquitination and lysosomal degradation of surface Kv7.1 (KCNQ1), reducing channel surface expression and currents; this pathway is activated during epithelial polarization downstream of PKC. Confocal microscopy, pharmacological AMPK activators, Xenopus oocyte electrophysiology, MDCK cell polarization model Traffic (Copenhagen, Denmark) Medium 21957902
2011 USP2 (deubiquitylating enzyme) counteracts Nedd4-2-mediated ubiquitination and downregulation of KCNQ1 by reducing covalent ubiquitin attachment, restoring KCNQ1 surface density and IKs current; USP2 binds KCNQ1 independently of the PY motif. Xenopus oocyte electrophysiology, Western blot, co-immunoprecipitation, immunocytochemistry in transfected cells Heart rhythm Medium 22024150
2012 KCNQ1 and hERG directly interact via their C-termini in intact heterologous cells and primary cardiomyocytes (demonstrated by FRET); cAMP elevation specifically reduces the extent of KCNQ1-hERG interactions by ~40%. Acceptor photobleach FRET in HEK cells and primary cardiomyocytes, cAMP analog and forskolin treatment American journal of physiology. Heart and circulatory physiology Medium 23241319
2015 KCNQ1 physically associates with β-catenin and E-cadherin at the plasma membrane in well-differentiated CRC cells; KCNQ1 knockdown causes β-catenin relocalization from the membrane, loss of epithelial phenotype, and increased invasion; KCNQ1 overexpression traps β-catenin at the plasma membrane and reduces Wnt/β-catenin target gene expression. ShRNA knockdown, KCNQ1 overexpression, confocal microscopy, spheroid assays, invasion assays, chromanol 293B inhibition in CRC cell lines Proceedings of the National Academy of Sciences of the United States of America Medium 28373572
2015 KCNE3 shifts the voltage dependence of KCNQ1 S4 movement to extreme hyperpolarized potentials via electrostatic interactions between KCNE3 residues D54 and D55 and R228 in S4, rendering KCNQ1/KCNE3 constitutively conducting in the physiological voltage range; KCNE3 primarily affects the voltage-sensing domain rather than directly affecting the gate. Voltage clamp fluorometry, site-directed mutagenesis, PIP2 depletion in Xenopus oocytes Proceedings of the National Academy of Sciences of the United States of America High 26668384
2015 PIP2-dependent coupling between the voltage sensor domain and the pore is especially prominent in Kv7.1 because direct S4-S5/S6 protein-protein interactions are weakened by electrostatic repulsion; a PIP2 binding site was identified on Kv7.1 involving residues critical for PIP2-dependent gating. Molecular dynamics simulations, experimental electrophysiology, mutagenesis Scientific reports Medium 25559286
2015 BACE1 physically interacts with KCNQ1 and modulates IKs channel gating in a β-subunit-like fashion (slowing KCNQ1 inactivation, slowing KCNQ1/KCNE1 activation kinetics) independently of BACE1 enzymatic activity; BACE1 is expressed in cardiac myocytes and atrial BACE1-deficient mice show decreased IKs. Co-immunoprecipitation, FRAP, whole-cell patch clamp in HEK293T cells, cardiomyocytes, and BACE1 knockout mice Journal of molecular and cellular cardiology Medium 26454161
2017 KCNE1 affects both S4 movement and the gate of KCNQ1, whereas KCNE3 primarily affects S4 movement and only indirectly affects the gate (requiring intact S4-to-gate coupling); a triple mutation in the KCNE3 transmembrane segment introduces KCNE1-like gating effects; differences at the external end of KCNE transmembrane segments underlie differential effects on the first S4 movement. Voltage clamp fluorometry, site-directed mutagenesis, PIP2 depletion in Xenopus oocytes Proceedings of the National Academy of Sciences of the United States of America High 28808020
2018 More than half of KCNQ1 loss-of-function mutations in the voltage sensor domain destabilize VSD structure, causing mistrafficking and proteasomal degradation; the S0 helix acts as a central scaffold organizing and stabilizing the KCNQ1 VSD; six mechanistic categories of VSD mutation dysfunction were defined. Cell surface expression assay (51 variants), proteasome inhibition, protein stability assays, functional channel data in mammalian cells Science advances High 29532034
2019 α1-adrenergic receptor (α1AAR and α1BAR) activation causes AP2/clathrin-dependent internalization of KCNQ1 via the AMPK/Nedd4-2 pathway; internalization requires PY and YXXΦ motifs in the KCNQ1 C-terminus and occurs independently of KCNE1 and of α1AR internalization. HaloTag surface labeling, confocal fluorescence microscopy, dominant-negative motif mutagenesis, rat neonatal cardiomyocytes Biochemical pharmacology Medium 31491415
2020 KCNQ1 antibodies act as agonists on IKs channels: they shift the voltage dependence of activation to more negative potentials, slow deactivation, and increase single-channel open time and open probability, reversing prolonged cardiac repolarization in LQT2 iPSC-cardiomyocytes. Purified antibodies, whole-cell patch clamp, single-channel recordings in CHO cells overexpressing IKs, action potential measurements in iPSC-cardiomyocytes Journal of the American College of Cardiology High 32354382
2020 Kv7.1 and KCNE1 do not assemble in the early secretory pathway; instead, they follow an unconventional secretory route bypassing the Golgi, targeting to ER-plasma membrane junctions where Kv7.1-KCNE1 assembly occurs. Confocal microscopy, FRAP, biochemical trafficking assays, brefeldin A and Golgi-disruption experiments Science advances Medium 32270035
2010 Epidermal growth factor receptor kinase phosphorylates KCNQ1 protein and upregulates IKs; genistein and tyrphostin AG556 suppress IKs by reducing KCNQ1 tyrosine phosphorylation, while orthovanadate (phosphatase inhibitor) reverses this; Src-family kinases reduce the current but do not phosphorylate KCNQ1 tyrosine. Perforated patch clamp, co-immunoprecipitation, Western blot with phospho-specific antibodies in HEK293 stable cells Biochimica et biophysica acta Medium 20085748

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature 1490 8900283
1996 K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature 1362 8900282
2000 Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 962 10973849
2003 KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science (New York, N.Y.) 788 12522251
1997 Human KVLQT1 gene shows tissue-specific imprinting and encompasses Beckwith-Wiedemann syndrome chromosomal rearrangements. Nature genetics 307 9020845
1997 KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. Circulation 265 9386136
1997 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. Human molecular genetics 248 9328483
2000 Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice. The Journal of clinical investigation 235 11120752
1997 Properties of KvLQT1 K+ channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias. The EMBO journal 232 9312006
2005 The KCNQ1 potassium channel: from gene to physiological function. Physiology (Bethesda, Md.) 229 16287990
1997 KvLQT1, a voltage-gated potassium channel responsible for human cardiac arrhythmias. Proceedings of the National Academy of Sciences of the United States of America 175 9108097
1998 Functional expression of two KvLQT1-related potassium channels responsible for an inherited idiopathic epilepsy. The Journal of biological chemistry 161 9677360
2003 Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT syndrome. Journal of the American College of Cardiology 156 12598076
2005 KCNQ1-dependent transport in renal and gastrointestinal epithelia. Proceedings of the National Academy of Sciences of the United States of America 153 16314573
1997 Pathophysiological mechanisms of dominant and recessive KVLQT1 K+ channel mutations found in inherited cardiac arrhythmias. Human molecular genetics 146 9302275
2007 The KCNQ1 (Kv7.1) COOH terminus, a multitiered scaffold for subunit assembly and protein interaction. The Journal of biological chemistry 118 18165683
1997 Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome. Circulation 107 9323054
1998 MinK-KvLQT1 fusion proteins, evidence for multiple stoichiometries of the assembled IsK channel. The Journal of biological chemistry 105 9852064
2001 Differential expression of KvLQT1 and its regulator IsK in mouse epithelia. American journal of physiology. Cell physiology 98 11208532
2013 The role of KCNQ1 in mouse and human gastrointestinal cancers. Oncogene 97 23975432
2008 Kv7.1 (KCNQ1) properties and channelopathies. The Journal of physiology 96 18174212
2011 Differential conditions for early after-depolarizations and triggered activity in cardiomyocytes derived from transgenic LQT1 and LQT2 rabbits. The Journal of physiology 95 22183728
1998 Activation and inactivation of homomeric KvLQT1 potassium channels. Biophysical journal 88 9675180
1999 Functional effects of mutations in KvLQT1 that cause long QT syndrome. Journal of cardiovascular electrophysiology 78 10376919
2018 Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations. Science advances 77 29532034
2000 MinK subdomains that mediate modulation of and association with KvLQT1. The Journal of general physiology 76 10962015
2021 Suppression-Replacement KCNQ1 Gene Therapy for Type 1 Long QT Syndrome. Circulation 74 33504163
2001 Cloning and function of the rat colonic epithelial K+ channel KVLQT1. The Journal of membrane biology 73 11220365
1998 New mutations in the KVLQT1 potassium channel that cause long-QT syndrome. Circulation 70 9570196
2002 Expression and coassociation of ERG1, KCNQ1, and KCNE1 potassium channel proteins in horse heart. American journal of physiology. Heart and circulatory physiology 69 12063283
2007 KCNQ1 mutation Q147R is associated with atrial fibrillation and prolonged QT interval. Heart rhythm 68 17997361
2005 Abnormal KCNQ1 trafficking influences disease pathogenesis in hereditary long QT syndromes (LQT1). Cardiovascular research 68 15935335
2000 Mechanisms of I(Ks) suppression in LQT1 mutants. American journal of physiology. Heart and circulatory physiology 68 11087258
2017 Bidirectional KCNQ1:β-catenin interaction drives colorectal cancer cell differentiation. Proceedings of the National Academy of Sciences of the United States of America 65 28373572
2013 KCNQ1 long QT syndrome patients have hyperinsulinemia and symptomatic hypoglycemia. Diabetes 64 24357532
2004 An LQT mutant minK alters KvLQT1 trafficking. American journal of physiology. Cell physiology 63 14761891
2010 R231C mutation in KCNQ1 causes long QT syndrome type 1 and familial atrial fibrillation. Heart rhythm 60 20850564
2003 KvLQT1 modulates the distribution and biophysical properties of HERG. A novel alpha-subunit interaction between delayed rectifier currents. The Journal of biological chemistry 58 14585842
2003 Location of mutation in the KCNQ1 and phenotypic presentation of long QT syndrome. Journal of cardiovascular electrophysiology 58 14678125
2001 Cocaine blocks HERG, but not KvLQT1+minK, potassium channels. Molecular pharmacology 57 11306689
2001 Characterization and subcellular localization of KCNQ1 with a heterozygous mutation in the C terminus. Journal of molecular and cellular cardiology 56 11162126
2000 Differential expression of KvLQT1 isoforms across the human ventricular wall. American journal of physiology. Heart and circulatory physiology 56 10843888
2006 The N-terminal juxtamembranous domain of KCNQ1 is critical for channel surface expression: implications in the Romano-Ward LQT1 syndrome. Circulation research 55 17053194
2001 AKAP proteins anchor cAMP-dependent protein kinase to KvLQT1/IsK channel complex. American journal of physiology. Heart and circulatory physiology 55 11299204
2015 Paternal allelic mutation at the Kcnq1 locus reduces pancreatic β-cell mass by epigenetic modification of Cdkn1c. Proceedings of the National Academy of Sciences of the United States of America 54 26100882
1999 Homozygous deletion in KVLQT1 associated with Jervell and Lange-Nielsen syndrome. Circulation 53 10077519
2008 IKs response to protein kinase A-dependent KCNQ1 phosphorylation requires direct interaction with microtubules. Cardiovascular research 51 18390900
2013 Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long-QT syndrome. Circulation. Cardiovascular genetics 50 23856471
2015 PIP₂-dependent coupling is prominent in Kv7.1 due to weakened interactions between S4-S5 and S6. Scientific reports 48 25559286
2009 Dynamic partnership between KCNQ1 and KCNE1 and influence on cardiac IKs current amplitude by KCNE2. The Journal of biological chemistry 48 19372218
2007 Involvement of KATP and KvLQT1 K+ channels in EGF-stimulated alveolar epithelial cell repair processes. American journal of physiology. Lung cellular and molecular physiology 48 17631610
2017 KCNE1 and KCNE3 modulate KCNQ1 channels by affecting different gating transitions. Proceedings of the National Academy of Sciences of the United States of America 47 28808020
2011 Protein kinase C downregulates I(Ks) by stimulating KCNQ1-KCNE1 potassium channel endocytosis. Heart rhythm 47 21699843
2002 Compound heterozygous mutations in KvLQT1 cause Jervell and Lange-Nielsen syndrome. Molecular genetics and metabolism 44 12051962
2006 Does pregnancy increase cardiac risk for LQT1 patients with the KCNQ1-A341V mutation? Journal of the American College of Cardiology 41 17010804
1997 P2U purinergic receptor inhibits apical IsK/KvLQT1 channel via protein kinase C in vestibular dark cells. The American journal of physiology 37 9435509
2018 Hypermethylated KCNQ1 acts as a tumor suppressor in hepatocellular carcinoma. Biochemical and biophysical research communications 36 30144972
2015 KCNE3 acts by promoting voltage sensor activation in KCNQ1. Proceedings of the National Academy of Sciences of the United States of America 34 26668384
1998 Genomic organization and mutational analysis of KVLQT1, a gene responsible for familial long QT syndrome. Human genetics 34 9799083
2020 Gating and Regulation of KCNQ1 and KCNQ1 + KCNE1 Channel Complexes. Frontiers in physiology 33 32581825
2011 AMP-activated protein kinase downregulates Kv7.1 cell surface expression. Traffic (Copenhagen, Denmark) 33 21957902
2001 Regulation and properties of KCNQ1 (K(V)LQT1) and impact of the cystic fibrosis transmembrane conductance regulator. The Journal of membrane biology 33 11426298
2010 Impact of KCNE subunits on KCNQ1 (Kv7.1) channel membrane surface targeting. Journal of cellular physiology 32 20533308
2008 Genomic structure, transcriptional control, and tissue distribution of HERG1 and KCNQ1 genes. American journal of physiology. Heart and circulatory physiology 32 18192214
2005 KCNQ1/KCNE1 channels during germ-cell differentiation in the rat: expression associated with testis pathologies. Journal of cellular physiology 30 15389592
2004 Additional gene variants reduce effectiveness of beta-blockers in the LQT1 form of long QT syndrome. Journal of cardiovascular electrophysiology 30 15028050
2004 Characterization of a KCNQ1/KVLQT1 polymorphism in Asian families with LQT2: implications for genetic testing. Journal of molecular and cellular cardiology 30 15242738
2020 The miR-140-5p/KLF9/KCNQ1 axis promotes the progression of renal cell carcinoma. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27 32596959
2013 A KCNQ1 mutation causes age-dependant bradycardia and persistent atrial fibrillation. Pflugers Archiv : European journal of physiology 27 23989646
2010 Mechanistic basis for LQT1 caused by S3 mutations in the KCNQ1 subunit of IKs. The Journal of general physiology 27 20421371
2014 Functional assembly of Kv7.1/Kv7.5 channels with emerging properties on vascular muscle physiology. Arteriosclerosis, thrombosis, and vascular biology 26 24855057
2011 Deubiquitylating enzyme USP2 counteracts Nedd4-2-mediated downregulation of KCNQ1 potassium channels. Heart rhythm 26 22024150
2014 Kcnq1-5 (Kv7.1-5) potassium channel expression in the adult zebrafish. BMC physiology 25 24555524
2012 Interactions between hERG and KCNQ1 α-subunits are mediated by their COOH termini and modulated by cAMP. American journal of physiology. Heart and circulatory physiology 25 23241319
1998 Novel donor splice site mutation in the KVLQT1 gene is associated with long QT syndrome. Journal of cardiovascular electrophysiology 25 9654228
1997 The long QT syndrome: a novel missense mutation in the S6 region of the KVLQT1 gene. Human genetics 25 9272155
2001 Expression and function of colonic epithelial KvLQT1 K+ channels. Clinical and experimental pharmacology & physiology 24 11153543
2010 Pore mutants of HERG and KvLQT1 downregulate the reciprocal currents in stable cell lines. American journal of physiology. Heart and circulatory physiology 23 20833965
2020 KCNQ1 Antibodies for Immunotherapy of Long QT Syndrome Type 2. Journal of the American College of Cardiology 22 32354382
2019 Upgraded molecular models of the human KCNQ1 potassium channel. PloS one 22 31518351
2015 BACE1 modulates gating of KCNQ1 (Kv7.1) and cardiac delayed rectifier KCNQ1/KCNE1 (IKs). Journal of molecular and cellular cardiology 21 26454161
2010 Regulation of human cardiac KCNQ1/KCNE1 channel by epidermal growth factor receptor kinase. Biochimica et biophysica acta 21 20085748
2010 Hypothyroidism of gene-targeted mice lacking Kcnq1. Pflugers Archiv : European journal of physiology 21 20978783
2008 LQT1-associated mutations increase KCNQ1 proteasomal degradation independently of Derlin-1. The Journal of biological chemistry 21 19114714
2002 KCNQ1 gene mutations and the respective genotype-phenotype correlations in the long QT syndrome. Medical science monitor : international medical journal of experimental and clinical research 20 12388934
2020 miR-483-5p promotes esophageal cancer progression by targeting KCNQ1. Biochemical and biophysical research communications 19 32819715
2011 Kv7.1 surface expression is regulated by epithelial cell polarization. American journal of physiology. Cell physiology 19 21228319
2006 Skipping of Exon 1 in the KCNQ1 gene causes Jervell and Lange-Nielsen syndrome. The Journal of biological chemistry 19 16987820
2022 Mutation-Specific Differences in Kv7.1 (KCNQ1) and Kv11.1 (KCNH2) Channel Dysfunction and Long QT Syndrome Phenotypes. International journal of molecular sciences 18 35806392
2015 Dual LQT1 and HCM phenotypes associated with tetrad heterozygous mutations in KCNQ1, MYH7, MYLK2, and TMEM70 genes in a three-generation Chinese family. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 18 25825456
2021 The history and geographic distribution of a KCNQ1 atrial fibrillation risk allele. Nature communications 16 34750360
2006 Protein distribution of Kcnq1, Kcnh2, and Kcne3 potassium channel subunits during mouse embryonic development. The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology 16 16463373
2020 The unconventional biogenesis of Kv7.1-KCNE1 complexes. Science advances 15 32270035
2019 Protein structure aids predicting functional perturbation of missense variants in SCN5A and KCNQ1. Computational and structural biotechnology journal 15 30828412
2019 KCNQ1 is internalized by activation of α1 adrenergic receptors. Biochemical pharmacology 14 31491415
2007 Human KCNQ1 S140G mutation is associated with atrioventricular blocks. Heart rhythm 14 17467630
2022 The Pathological Mechanisms of Hearing Loss Caused by KCNQ1 and KCNQ4 Variants. Biomedicines 13 36140355
2021 ML277 regulates KCNQ1 single-channel amplitudes and kinetics, modified by voltage sensor state. The Journal of general physiology 13 34636894
2012 Regulation of KCNQ1/KCNE1 by β-catenin. Molecular membrane biology 13 22583083
2005 Effects of epinephrine on right ventricular monophasic action potentials in the LQT1 versus LQT2 form of long QT syndrome: preferential enhancement of "triangulation" in LQT1. Pacing and clinical electrophysiology : PACE 13 15733182

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