{"gene":"PKD2","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1996,"finding":"PKD2 encodes a predicted 968-amino acid integral membrane protein with six transmembrane spans, intracellular amino- and carboxyl-termini, similarity to voltage-activated calcium channels, and a potential calcium-binding domain.","method":"Positional cloning, sequence analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — original positional cloning with sequence characterization, foundational paper replicated across the field","pmids":["8650545"],"is_preprint":false},{"year":1997,"finding":"PKD1 and PKD2 proteins interact through their C-terminal cytoplasmic tails; the PKD2 C-terminal cytoplasmic tail forms homodimers through a coiled-coil domain distinct from the PKD1 interaction region; PKD1-PKD2 interaction upregulates PKD1 expression.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro binding","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and yeast two-hybrid, independently replicated in multiple subsequent studies","pmids":["9192675"],"is_preprint":false},{"year":1998,"finding":"Somatic inactivation (loss of both alleles) of Pkd2 is necessary and sufficient for renal cyst formation in mice, establishing a cellular recessive (two-hit) mechanism for ADPKD type 2.","method":"Mouse genetics — unstable allele with intragenic homologous recombination, immunohistochemistry for Pkd2 expression in cysts","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse knockout model with loss-of-function phenotype and protein expression validation, broadly replicated","pmids":["9568711"],"is_preprint":false},{"year":1999,"finding":"Polycystin-2 is an ~110-kDa integral membrane glycoprotein that localizes predominantly to the endoplasmic reticulum in native tissues and cultured cells. A 34-amino acid region (Glu787–Ser820) in the C-terminal tail is responsible for exclusive ER retention and mediates interaction with an unidentified ER-binding partner; truncation at or before Glu787 allows plasma membrane trafficking.","method":"Immunofluorescence, co-localization with PDI/calnexin, subcellular fractionation, Endo H sensitivity, cell-surface biotinylation, truncation mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (fractionation, Endo H, biotinylation, mutagenesis) in a single rigorous study","pmids":["10497221"],"is_preprint":false},{"year":1999,"finding":"PKD2 protein directly associates with TRPC1 (but not TRPC3) via two distinct domains: a 73-amino acid region in the C-terminal cytoplasmic tail and a more N-terminal domain within transmembrane segments S2–S5 including the putative pore region.","method":"Co-immunoprecipitation in transfected cells and in vitro binding assay, deletion mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP in cells plus in vitro binding, single lab, two orthogonal methods","pmids":["10097141"],"is_preprint":false},{"year":2000,"finding":"PKD2 interacts with Hax-1 (a protein associated with the actin cytoskeleton) via its C-terminal domain, and Hax-1 associates with the F-actin-binding protein cortactin, providing a molecular link between PKD2 and the actin cytoskeleton. PKD2 and Hax-1 co-localize in the cell body and in cellular processes/lamellipodia.","method":"Yeast two-hybrid screen, immunofluorescence co-localization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid plus co-localization, no reciprocal Co-IP or functional validation of interaction in mammalian cells","pmids":["10760273"],"is_preprint":false},{"year":2000,"finding":"Polycystin-2 localizes to the basolateral plasma membrane of kidney tubular epithelial cells in vivo, distinct from the junctional localization of polycystin-1, suggesting independent as well as overlapping functions.","method":"Immunohistochemistry and immunofluorescence microscopy of human and murine renal tissues","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunofluorescence and IHC in native tissues, single lab, two tissue preparation methods","pmids":["10770959"],"is_preprint":false},{"year":2004,"finding":"PKD2 interacts with mDia1 (a RhoA GTPase-binding formin) via the PKD2 C-terminus binding to the mDia1 N-terminus. This interaction localizes PKD2 to mitotic spindles in dividing cells; RNAi knockdown of mDia1 causes loss of PKD2 from spindles and alters intracellular Ca2+ release.","method":"Yeast two-hybrid, co-immunoprecipitation in native and transfected cells, immunofluorescence, RNAi knockdown, Ca2+ imaging","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP in native cells plus RNAi functional validation, single lab, multiple orthogonal methods","pmids":["15123714"],"is_preprint":false},{"year":2005,"finding":"PKD2 (TRPP2) subcellular localization and trafficking are regulated by phosphofurin acidic cluster sorting proteins PACS-1 and PACS-2, which bind an acidic cluster in the PKD2 C-terminal domain. This binding is regulated by casein kinase 2-mediated phosphorylation (at Ser812), directing PKD2 routing between ER, Golgi, and plasma membrane.","method":"Co-immunoprecipitation, phosphorylation assays, subcellular fractionation, mutagenesis (Ser812Ala), functional electrophysiology","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution of phosphorylation-dependent binding with mutagenesis plus functional channel assays, multiple orthogonal methods","pmids":["15692563"],"is_preprint":false},{"year":2005,"finding":"PKD2 functions as an EGF-activated plasma membrane cation channel. EGF activates PKD2 via PLC and PI3K signaling, independently of store depletion. PIP2 negatively regulates PKD2 channel activity. PKD2 physically interacts with PLC-γ2 and EGFR and co-localizes with EGFR and PIP2 in the primary cilium.","method":"Electrophysiology (whole-cell patch clamp), RNAi knockdown, PIP2/PIP3 pipette infusion, pharmacology, co-immunoprecipitation, immunofluorescence","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods including electrophysiology, RNAi, biochemical interaction, and pharmacology in a single study","pmids":["16135816"],"is_preprint":false},{"year":2007,"finding":"In Chlamydomonas reinhardtii, CrPKD2 moves bidirectionally in the flagellar membrane and its flagellar entry and abundance require intraflagellar transport (IFT). Flagellar CrPKD2 increases fourfold during gametogenesis, and RNAi strains show defects in flagella-dependent mating, indicating PKD2 couples flagellar adhesion to Ca2+ signaling during mating.","method":"GFP live imaging, FRAP, IFT block experiments, RNAi, mating assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live imaging and FRAP with functional RNAi validation, ortholog study in Chlamydomonas","pmids":["17984324"],"is_preprint":false},{"year":2008,"finding":"TRPP2 and TRPC1 assemble to form a heteromeric receptor-operated channel with a 2:2 stoichiometry and alternating subunit arrangement, exhibiting unique single-channel conductance, amiloride sensitivity, and ion permeability profiles distinct from either subunit alone. Endogenous TRPP2/TRPC1 activity occurs in kidney cells and both subunits co-localize at the primary cilium.","method":"Electrophysiology, co-immunoprecipitation from kidney membranes, gain/loss-of-function experiments, immunofluorescence, atomic force microscopy","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (electrophysiology, AFM structural analysis, Co-IP from native tissue, gain/loss-of-function), replicated across papers","pmids":["18323855","19850920"],"is_preprint":false},{"year":2009,"finding":"ER-localized TRPP2 reduces the Ca2+ concentration in the ER by increasing ER Ca2+ permeability, thereby counteracting SERCA activity and reducing IP3R-mediated Ca2+ release. This protects cells from apoptosis; TRPP2 knockdown in renal epithelial cells increases ER Ca2+ release and augments apoptotic sensitivity.","method":"Ca2+ imaging, RNAi knockdown, apoptosis assays, pharmacology (thapsigargin, IP3R agonists)","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional Ca2+ measurements with RNAi knockdown and pharmacological validation, single lab","pmids":["19153608"],"is_preprint":false},{"year":2009,"finding":"The TRPP2/PKD1 complex contains 3 TRPP2 and 1 PKD1 subunits. A newly identified coiled-coil domain in the TRPP2 C-terminus forms a homotrimer (confirmed by crystallography) that binds a single PKD1 C-terminal coiled-coil. Mutations disrupting the TRPP2 coiled-coil trimer abolish complex assembly and reduce surface expression of both proteins.","method":"Biochemistry, X-ray crystallography, single-molecule subunit counting in live cells (fluorescence), mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus single-molecule counting and mutagenesis functional validation in one study","pmids":["19556541"],"is_preprint":false},{"year":2009,"finding":"PKD2/TRPP2 forms homotetramers and heteromeric complexes with TRPC1 in a tetrameric configuration. In homomeric PC2 channels, four subconductance states follow staircase behavior that is pH- and voltage-dependent; low pH inhibits homomeric but not heteromeric PC2/TRPC1 complexes, demonstrating distinct functional properties between homo- and heteromeric assemblies.","method":"Single-channel electrophysiology, atomic force microscopy, kinetic analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — electrophysiology plus AFM structural analysis, single lab","pmids":["19193631"],"is_preprint":false},{"year":2010,"finding":"A coiled-coil domain in the PKD2 C-terminus functions as an essential homodimerization domain required for PC1 binding but not for PKD2 self-oligomerization. Dimerization-defective PKD2 mutants cannot reconstitute PC1/PC2 complexes at the plasma membrane or ER-PM junctions but retain ER Ca2+-release channel function. Expression of these mutants in zebrafish produces cystic phenotype.","method":"Mutagenesis, co-immunoprecipitation, electrophysiology, zebrafish in vivo rescue","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis with biochemical, electrophysiological, and in vivo validation across multiple orthogonal methods","pmids":["20168298"],"is_preprint":false},{"year":2010,"finding":"TRPP2 interacts with TRPV4 (but not TRPA1 or TRPM8), forming a heterotetramer with 2:2 stoichiometry and alternating subunit arrangement, analogous to the TRPP2-TRPC1 heteromer.","method":"Co-immunoprecipitation, atomic force microscopy with antibody labeling","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus AFM structural analysis, single lab, two orthogonal methods","pmids":["20682256"],"is_preprint":false},{"year":2010,"finding":"Protein kinase D phosphorylates polycystin-2 at Ser801 in the C-terminus; this phosphorylation is stimulated by serum/EGF, is required for PKD2-mediated inhibition of cell proliferation, and for ATP-stimulated ER Ca2+ release. A pathogenic ADPKD mutation (S804N) abolishes Ser801 phosphorylation.","method":"Mutagenesis, in vitro kinase assay, Ca2+ imaging, cell proliferation assay, Western blot","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and functional validation, single lab","pmids":["20881056"],"is_preprint":false},{"year":2010,"finding":"PRKCSH binds the C-terminal domain of TRPP2 in the ER and inhibits HERP-mediated ubiquitination of TRPP2, protecting it from ER-associated degradation. Loss of PRKCSH leads to reduced TRPP2 levels and cyst formation in zebrafish.","method":"Co-immunoprecipitation, ubiquitination assay, zebrafish knockdown/rescue experiments","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with ubiquitination assay and in vivo zebrafish validation, single lab","pmids":["19801576"],"is_preprint":false},{"year":2011,"finding":"Pkd1l1 physically interacts with Pkd2 and both co-localize to cilia of the embryonic node. Pkd1l1 and Pkd2 point mutants phenocopy each other (right isomerism, failure to activate asymmetric gene expression), establishing Pkd1l1 as a Pkd2 binding partner required for L-R patterning downstream of nodal flow.","method":"Co-immunoprecipitation, immunofluorescence co-localization in node cilia, genetic epistasis (parallel mutant phenotyping)","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP plus in vivo genetic epistasis replicated in two independent studies (mouse and medaka)","pmids":["21307093","21307098"],"is_preprint":false},{"year":2011,"finding":"The TRPP2/PKD1 C-terminal coiled-coil complex forms a novel di-trimer configuration (upstream trimer of three TRPP2 helices; downstream trimer of two TRPP2 and one PKD1 helix). Mutagenesis of critical interface positions abolishes heteromeric coiled-coil complex assembly in full-length proteins in cells.","method":"Computational docking based on crystal structure of TRPP2 coiled-coil trimer, mutagenesis, biochemical co-immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — structure-based computational model validated by mutagenesis and biochemistry, single lab","pmids":["21642537"],"is_preprint":false},{"year":2011,"finding":"Cys632 in the PKD2 extracellular loop constitutes a third homodimerization domain via disulfide bond formation. Combined disruption of Cys632 and the C-terminal coiled-coil domain nearly abolishes homodimer formation and ER Ca2+ release, but C632A mutant retains ability to heterodimerize with PKD1.","method":"Mutagenesis, non-reducing SDS-PAGE, co-immunoprecipitation, Ca2+ imaging (ATP-stimulated ER Ca2+ release)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis with biochemical and functional Ca2+ validation, single lab","pmids":["21474446"],"is_preprint":false},{"year":2013,"finding":"TRPP2 and TRPV4 assemble to form a 23-pS divalent cation-permeable non-selective ion channel at the apical membrane of renal collecting duct principal cells. This channel is activated by EGF via EGFR tyrosine kinase signaling; loss of either subunit reduces the 23-pS channel activity.","method":"Patch-clamp electrophysiology, immunofluorescence, co-immunoprecipitation, shRNA knockdown","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — patch-clamp electrophysiology with Co-IP and RNAi, single lab","pmids":["23977387"],"is_preprint":false},{"year":2013,"finding":"TRPP2 is expressed in cerebral artery smooth muscle cells, residing primarily (~88%) in the plasma membrane. TRPP2 mediates stretch-activated cation currents (ICat), and its knockdown reduces myogenic tone at intravascular pressures of 40–100 mmHg without altering depolarization-induced vasoconstriction.","method":"Arterial biotinylation, immunofluorescence, patch-clamp electrophysiology, RNAi knockdown, pressure myography","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (biotinylation, electrophysiology, RNAi, myography), single lab","pmids":["23858011"],"is_preprint":false},{"year":2014,"finding":"TRPV4, TRPC1, and TRPP2 assemble to form a heteromeric channel complex; all three subunits contribute to the ion permeation pore. This heteromeric channel mediates flow-induced Ca2+ influx in native vascular endothelial cells.","method":"Two-step co-immunoprecipitation, FRET, patch-clamp electrophysiology with pore-dead mutants, Ca2+ imaging","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two-step Co-IP plus FRET plus functional electrophysiology with pore-dead mutants, single lab","pmids":["25114176"],"is_preprint":false},{"year":2014,"finding":"Native TRPP2 is N-glycosylated at five asparagines in the first extracellular loop. Glycosylation is required for efficient TRPP2 biogenesis; mutation of glycosylated asparagines severely reduces protein expression. Glucosidase II (GIIβ/PRKCSH) mediates glycan trimming of TRPP2, and impaired trimming reduces TRPP2 abundance.","method":"Mass spectrometry, mutagenesis, Western blot, pharmacological inhibition of lysosomal degradation, genetic (Prkcsh-/- mice)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mass spectrometry identification plus mutagenesis and genetic validation in knockout mice, multiple orthogonal methods","pmids":["24719335"],"is_preprint":false},{"year":2015,"finding":"Trpp2 (together with Trpv4) mediates endocardial calcium responses to oscillatory flow and is required for klf2a mechanosensitive expression and heart valve morphogenesis in zebrafish. Absence of Trpp2 leads to valve defects.","method":"Live Ca2+ imaging, klf2a promoter reporter assay, morpholino knockdown in zebrafish, mathematical flow modeling","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging with Ca2+ reporter and promoter assay plus in vivo knockdown, single lab","pmids":["25959969"],"is_preprint":false},{"year":2015,"finding":"Pkd2 localizes to primary cilia of radial glia cells (RGCs) in the brain ventricular epithelium; conditional ablation of Pkd2 disrupts planar cell polarity (PCP) development in RGCs and ependymal cells and impairs asymmetric localization of PCP protein Vangl2, implicating Pkd2 in mechanosensory-driven PCP establishment.","method":"Immunofluorescence, conditional Cre-lox knockout (Nestin-Cre;Pkd2flox/flox), double-heterozygous epistasis (Pkd1 × Vangl2)","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout with genetic epistasis and immunofluorescence, single lab","pmids":["26245976"],"is_preprint":false},{"year":2015,"finding":"PKA directly phosphorylates polycystin-2 at Ser829 in the C-terminus; this increases channel mean open time without altering single-channel conductance. The phosphorylation is reversed by alkaline phosphatase. A truncation at Arg742 or mutation S829A abolishes PKA-mediated channel activation.","method":"Lipid bilayer reconstitution, in vitro PKA phosphorylation, mutagenesis (S829A, R742X), electrophysiology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with PKA plus mutagenesis and single-channel electrophysiology, rigorous controls","pmids":["26269590"],"is_preprint":false},{"year":2016,"finding":"A constitutively active gain-of-function TRPP2 mutant (S4-S5 linker/S5 domain) revealed that extracellular divalent ions (including Ca2+) inhibit monovalent ion permeation by directly blocking the TRPP2 channel pore, and that D643 (a negatively charged pore residue) is crucial for channel permeability.","method":"Mutagenesis scanning, electrophysiology, zebrafish rescue experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — structure-guided mutagenesis with electrophysiology and in vivo zebrafish validation, multiple methods","pmids":["27071085"],"is_preprint":false},{"year":2016,"finding":"The native TRPP2-dependent channel in murine renal primary cilia is a large-conductance cation channel (97–189 pS) permeable to K+, Ca2+, and Na+ with permeability ratios PK:PCa:PNa of 1:0.55:0.14. Open probability increases with membrane depolarization or elevated cytoplasmic Ca2+. CRISPR/Cas9 knockout of TRPP2 eliminates this channel current.","method":"Direct electrophysiology from isolated primary cilia, CRISPR/Cas9 gene editing","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct ciliary patch-clamp with CRISPR knockout confirmation, rigorous electrophysiological characterization","pmids":["27760766"],"is_preprint":false},{"year":2018,"finding":"The cryo-EM structure of the human PKD1-PKD2 complex at 3.6 Å reveals a 1:3 (PKD1:PKD2) ratio with domain-swapped, noncanonical TRP channel architecture. PKD1 contains a VGIC fold; its S6 helix is broken into S6a (resembling pore helix 1) and S6b (with three positively charged cavity-facing residues that may block cation permeation). Additional resolved domains include a five-TM helix domain and a cytosolic PLAT domain in PKD1.","method":"Cryo-electron microscopy at 3.6 Å resolution","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure providing direct atomic-level insight into complex architecture","pmids":["30093605"],"is_preprint":false},{"year":2018,"finding":"PKD2 channels in arterial smooth muscle cells are modified by SUMO1 at physiological intravascular pressures. SUMOylated PKD2 (SUMO-PKD2) recycles between intracellular compartments and the plasma membrane, while unmodified PKD2 is surface-resident. Intravascular pressure activates voltage-dependent Ca2+ influx that stimulates SUMO-PKD2 recycling to the surface; desumoylation eliminates pressure-activated INa and causes vasodilation.","method":"Cell-specific inducible Pkd2 knockout mice, SUMO modification assays, patch-clamp electrophysiology, pressure myography","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible cell-specific KO with biochemical SUMOylation assay, electrophysiology, and functional vascular assays, multiple orthogonal methods","pmids":["31822608"],"is_preprint":false},{"year":2018,"finding":"SLC25A25, a Ca2+-regulated mitochondrial ATP-Mg/Pi solute carrier, acts downstream of TRPP2-mediated ciliary Ca2+ signals. Identified by a genome-wide forward genetic screen in Drosophila and validated in zebrafish left-right patterning, establishing an evolutionarily conserved link between TRPP2 ciliary signaling and mitochondrial metabolism.","method":"Genome-wide forward genetic screen (Drosophila), zebrafish targeted knockdown with left-right patterning readout","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased genetic screen plus targeted in vivo validation in two organisms, single lab","pmids":["30080851"],"is_preprint":false},{"year":2020,"finding":"Intravascular flow activates endothelial PKD2 channels, leading to Ca2+ influx that activates SK/IK channels and eNOS phosphorylation at Ser1176, producing arterial hyperpolarization and vasodilation. EC-specific Pkd2 knockout elevates blood pressure without altering cardiac function or kidney anatomy.","method":"Inducible EC-specific Pkd2 knockout mice, patch-clamp electrophysiology, eNOS phosphorylation assay, pressure myography, blood pressure telemetry","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible EC-specific KO with electrophysiology, signaling assays, and in vivo blood pressure measurement, multiple orthogonal methods","pmids":["32364494"],"is_preprint":false},{"year":2020,"finding":"The heteromeric PC-1/PC-2 polycystin complex reconstituted in the plasma membrane functions as an outwardly rectifying channel. A soluble fragment generated from autoproteolytic cleavage of the PC-1 N-terminal extracellular domain acts as an intrinsic agonist that is necessary and sufficient for channel activation of both reconstituted and native ciliary polycystin channels.","method":"Reconstitution of PC-1/PC-2 complex in mammalian plasma membrane, electrophysiology, application of soluble PC-1 N-terminal fragment, ciliary patch-clamp","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional reconstitution plus ciliary electrophysiology with defined agonist, multiple orthogonal approaches","pmids":["33164752"],"is_preprint":false},{"year":2020,"finding":"PKD2 forms a protein complex with BECN1 (beclin-1) via the CC1 coiled-coil domain in the PKD2 C-terminus, inducing autophagy. This interaction depends on PKD2 Ca2+ channel activity; a channel-dead mutant (D509V) shows diminished BECN1 binding and fails to induce autophagy. Depletion of intracellular Ca2+ (BAPTA-AM) disrupts the PKD2-BECN1 complex and blocks starvation-induced autophagy.","method":"Co-immunoprecipitation, mutagenesis (CC1 deletion, D509V), autophagy assays (LC3 II/I, autophagosomes), BAPTA-AM Ca2+ chelation","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis and functional autophagy validation, single lab, multiple orthogonal methods","pmids":["32543276"],"is_preprint":false},{"year":2020,"finding":"Chlamydomonas PKD2 targets and anchors mastigonemes (MST1 glycoprotein filamentous polymers) to the extracellular surface of cilia. PKD2-mastigoneme complexes connect to axonemal doublets 4 and 8; pkd2 mutant cilia lack mastigonemes and cells swim with reduced velocity, suggesting a mechanosensory role.","method":"Immunofluorescence, electron microscopy, genetic analysis of pkd2 mutants, motility assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct structural imaging plus genetic loss-of-function with functional readout, single lab in Chlamydomonas ortholog","pmids":["32348466"],"is_preprint":false},{"year":2019,"finding":"The large-conductance TRPP2-dependent channel in renal primary cilia also requires TRPM3; pharmacological activation with the TRPM3 agonist pregnenolone sulfate greatly enhances channel activity, and the specific TRPM3 inhibitor isosakuranetin blocks the channel. CRISPR/Cas9 knockout of TRPM3 eliminates the ciliary channel without altering ciliary TRPP2 protein levels.","method":"Direct ciliary electrophysiology, pharmacology (pregnenolone sulfate, isosakuranetin), CRISPR/Cas9 knockout of TRPM3, Western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct electrophysiology with pharmacology and genetic CRISPR knockout, single lab","pmids":["30883612"],"is_preprint":false},{"year":2018,"finding":"PKD2 channels in arterial smooth muscle cells are activated by intravascular pressure and α1-adrenoceptors, mediating an inward Na+ current that causes membrane depolarization and vasoconstriction. Inducible smooth muscle-specific PKD2 knockout lowers physiological blood pressure, reduces hypertension, and prevents pathological arterial remodeling.","method":"Inducible smooth muscle-specific Pkd2 knockout mice, patch-clamp electrophysiology, pressure myography, blood pressure telemetry","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible cell-type-specific KO with electrophysiology and in vivo blood pressure/vascular phenotyping, multiple orthogonal methods","pmids":["30511640"],"is_preprint":false},{"year":2022,"finding":"Fission yeast Pkd2 (polycystin homolog) permeates calcium when the membrane is stretched. In vitro reconstitution in giant unilamellar vesicles demonstrated Ca2+ permeability upon hypoosmotic shock; in vivo, pkd2 temperature-sensitive and hypomorphic mutants reduced intracellular Ca2+ levels and diminished cytokinesis-associated Ca2+ spikes, establishing Pkd2 as a mechanosensitive Ca2+-permeable channel activated by membrane stretching.","method":"Cell-free expression/reconstitution in GUVs, Ca2+ imaging in mutant yeast cells, hypoosmotic shock experiments","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution plus in vivo genetic validation, single lab, ortholog study in fission yeast","pmids":["36200871"],"is_preprint":false},{"year":2008,"finding":"The subcellular localization of TRPP2 determines its function: ER-localized TRPP2 (Ser812Asp, PACS-trapped) more effectively rescues left-right asymmetry defects in TRPP2-deficient zebrafish, while plasma membrane-directed TRPP2 (Ser812Ala) rescues cyst formation. This indicates that TRPP2 assumes distinct compartment-specific roles.","method":"PACS-binding mutagenesis (Ser812Ala, Ser812Asp), zebrafish knockdown/rescue experiments, immunofluorescence","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with in vivo zebrafish rescue using distinct functional readouts, single lab","pmids":["18417723"],"is_preprint":false},{"year":2003,"finding":"Drosophila Pkd2 is required for directional sperm movement inside the female reproductive tract. Targeted disruption causes male sterility without affecting spermatogenesis; mutant sperm are motile but fail to enter female storage organs, demonstrating PKD2 cation channel function in sperm flagella for directed movement.","method":"Genetic disruption (targeted P-element excision), fertility assays, sperm motility analysis, immunolocalization","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with specific behavioral/cellular phenotype in Drosophila ortholog, single lab","pmids":["14680633"],"is_preprint":false},{"year":2004,"finding":"Drosophila Pkd2 loss-of-function severely reduces visceral smooth muscle contractility, which is rescued by muscle-specific Pkd2 expression. Pkd2 genetically interacts with the ryanodine receptor to regulate skeletal muscle Ca2+ oscillation during excitation-contraction coupling; Pkd2 is haploinsufficient for normal smooth muscle contractility.","method":"Genetic loss-of-function, tissue-specific rescue (Gal4/UAS), pharmacological perturbation (ryanodine), genetic interaction analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis and tissue-specific rescue with functional readout, single lab in Drosophila ortholog","pmids":["14732716"],"is_preprint":false},{"year":2009,"finding":"Conditional loss of Pkd2 causes beta-catenin upregulation, as well as increased axin2 and cMyc expression, in renal collecting duct cells. Pkd2-null immortalized collecting duct cells show aberrant cell-cell contact, ciliogenesis, and tubulomorphogenesis, linking PC2 loss to dysregulation of beta-catenin-dependent signaling.","method":"Cre-loxP conditional knockout, Western blot, immunofluorescence, tubulomorphogenesis assay","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout with defined molecular and cellular phenotypes, single lab","pmids":["19939939"],"is_preprint":false},{"year":2008,"finding":"Polycystin-2 (TRPP2) channel activity in human syncytiotrophoblast apical membranes is rapidly and completely inhibited by reactive oxygen species (H2O2, tBHP) applied to the intracellular side (IC50 ~131 nM in native membranes), with inhibition mediated by targeting both membrane lipids (lipid peroxidation) and the channel protein itself.","method":"Lipid bilayer reconstitution, electrophysiology, TBARS measurement, catalase treatment","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct electrophysiology in reconstituted native membranes with dose-response, single lab","pmids":["18417208"],"is_preprint":false}],"current_model":"PKD2 encodes polycystin-2 (TRPP2), a Ca2+-permeable nonselective cation channel with six transmembrane domains that forms a 1:3 heteromeric receptor/ion channel complex with PKD1 (resolved by cryo-EM at 3.6 Å), and also assembles into homotetramers and heteromeric channels with TRPC1, TRPV4, and TRPM3. Its subcellular localization—ER, plasma membrane, or primary cilium—is regulated by CK2-mediated phosphorylation of Ser812 and PACS adaptor protein binding, with compartment-specific functions: at the ER it modulates luminal Ca2+ to regulate apoptosis and autophagy (via BECN1 interaction); at the plasma membrane it mediates mechanosensitive cation currents activated by flow, pressure, or EGF/PLC/PI3K signaling (negatively regulated by PIP2) to control vascular tone, blood pressure, and endothelial eNOS activation; and in primary cilia it forms a large-conductance (TRPM3-containing) channel required for mechanosensation and left-right axis determination (through interaction with Pkd1l1). SUMO1 modification of PKD2 in arterial myocytes regulates its surface density and pressure-dependent activation, while N-glycosylation at five extracellular asparagines and glycan trimming by GII/PRKCSH control its biogenesis and stability. Somatic biallelic inactivation of PKD2 in renal tubular cells is necessary and sufficient for cyst formation, establishing a cellular recessive two-hit mechanism for ADPKD."},"narrative":{"mechanistic_narrative":"PKD2 encodes polycystin-2 (TRPP2), a Ca2+-permeable nonselective cation channel with six transmembrane spans and intracellular N- and C-termini that operates across multiple cellular compartments to transduce mechanical and chemical signals into Ca2+ flux [PMID:8650545, PMID:27071085]. Its defining partnership is with PKD1 (polycystin-1): the two associate through C-terminal coiled-coil interactions, with the TRPP2 C-terminus forming a homotrimer that binds a single PKD1 coiled-coil to build a 1:3 (PKD1:TRPP2) complex, an arrangement resolved by cryo-EM as a domain-swapped, noncanonical TRP architecture [PMID:9192675, PMID:19556541, PMID:30093605]. Channel assembly is further organized by a Cys632 extracellular disulfide and the C-terminal coiled-coil, and disrupting these abolishes homodimerization and complex formation [PMID:20168298, PMID:21474446]. Beyond PKD1, TRPP2 assembles into homotetramers and heteromeric channels with TRPC1, TRPV4, and TRPM3, each with distinct conductance and permeation properties, and these complexes mediate flow-induced Ca2+ influx in endothelium and ciliary mechanosensation [PMID:18323855, PMID:19850920, PMID:19193631, PMID:20682256, PMID:25114176, PMID:30883612]. TRPP2 localization—ER, basolateral plasma membrane, or primary cilium—is set by a C-terminal acidic-cluster signal whose CK2-dependent phosphorylation at Ser812 controls PACS adaptor binding and routing, and these compartments correspond to distinct functions: ER-localized TRPP2 lowers luminal Ca2+ to limit IP3R-mediated release and apoptosis and binds BECN1 to drive autophagy, while plasma-membrane channels carry mechanosensitive and EGF/PLC/PI3K-activated cation currents [PMID:10497221, PMID:15692563, PMID:16135816, PMID:19153608, PMID:32543276, PMID:18417723]. Channel gating is tuned by PKA, PKD, and CK2 phosphorylation of the C-terminus and by SUMO1 modification that controls surface density in arterial myocytes [PMID:20881056, PMID:26269590, PMID:31822608], and biogenesis depends on N-glycosylation and PRKCSH/glucosidase-II-mediated glycan trimming that protect TRPP2 from ER-associated degradation [PMID:19801576, PMID:24719335]. In vascular smooth muscle and endothelium, pressure- and flow-activated PKD2 channels control myogenic tone, eNOS-dependent vasodilation, and blood pressure [PMID:32364494, PMID:30511640], and in cilia the TRPP2-dependent channel directs left-right axis determination through Pkd1l1 [PMID:21307093, PMID:21307098]. Somatic biallelic inactivation of Pkd2 in renal tubular cells is necessary and sufficient for cyst formation, establishing a cellular recessive two-hit mechanism for autosomal dominant polycystic kidney disease [PMID:9568711].","teleology":[{"year":1996,"claim":"Established the molecular identity of PKD2 as a membrane protein, framing it as a candidate channel rather than an unknown disease gene.","evidence":"Positional cloning and sequence analysis revealing six transmembrane spans and similarity to voltage-gated Ca2+ channels","pmids":["8650545"],"confidence":"High","gaps":["Sequence prediction alone did not demonstrate channel activity","No subcellular localization or partner identified"]},{"year":1997,"claim":"Defined the central PKD1-PKD2 partnership and the C-terminal coiled-coil that mediates it, explaining why mutations in either gene cause the same disease.","evidence":"Yeast two-hybrid, co-immunoprecipitation, and in vitro binding mapping the interacting C-terminal tails","pmids":["9192675"],"confidence":"High","gaps":["Stoichiometry of the complex not resolved","Functional consequence for channel activity not tested"]},{"year":1998,"claim":"Demonstrated the cellular genetic basis of ADPKD, showing cyst formation follows a recessive two-hit loss of Pkd2 within tubular cells.","evidence":"Mouse unstable-allele genetics with intragenic recombination and Pkd2 immunohistochemistry in cysts","pmids":["9568711"],"confidence":"High","gaps":["Downstream signaling driving cyst growth not defined","Cell-of-origin timing not addressed"]},{"year":1999,"claim":"Localized polycystin-2 predominantly to the ER and identified the C-terminal retention signal, raising the question of how it reaches the plasma membrane and cilium.","evidence":"Immunofluorescence, fractionation, Endo H sensitivity, biotinylation, and truncation mutagenesis","pmids":["10497221"],"confidence":"High","gaps":["Identity of the ER-binding partner unresolved at this stage","Mechanism of regulated export not known"]},{"year":2005,"claim":"Showed that compartmental routing is actively regulated by CK2 phosphorylation of Ser812 and PACS adaptor binding, providing a switch between ER, Golgi, and plasma membrane pools.","evidence":"Co-IP, phosphorylation assays, Ser812Ala mutagenesis, fractionation, and electrophysiology","pmids":["15692563"],"confidence":"High","gaps":["Upstream signals controlling CK2 activity on PKD2 not defined","How routing couples to physiological demand unclear"]},{"year":2008,"claim":"Linked subcellular localization to distinct physiological outputs, showing ER-trapped versus plasma-membrane TRPP2 rescue different defects.","evidence":"Ser812Ala/Ser812Asp mutagenesis with zebrafish rescue of left-right asymmetry versus cyst phenotypes","pmids":["18417723"],"confidence":"Medium","gaps":["Molecular effectors at each compartment not fully mapped","Quantitative partitioning between pools in native cells unknown"]},{"year":2009,"claim":"Resolved the architecture of the PKD1-PKD2 complex as a 3:1 trimer-of-TRPP2 binding one PKD1, defining the assembly rule for the complex.","evidence":"Crystallography of the TRPP2 C-terminal coiled-coil, single-molecule subunit counting, and mutagenesis","pmids":["19556541"],"confidence":"High","gaps":["Full transmembrane architecture not resolved at this stage","Gating mechanism of the assembled complex unknown"]},{"year":2009,"claim":"Established a direct ER function for TRPP2 in lowering luminal Ca2+ to counteract SERCA and limit apoptotic Ca2+ release.","evidence":"Ca2+ imaging, RNAi knockdown, apoptosis assays, and pharmacology in renal epithelial cells","pmids":["19153608"],"confidence":"Medium","gaps":["Direct demonstration of TRPP2 as the ER Ca2+ conductance not fully isolated from partners","Relationship to cyst pathology not established"]},{"year":2010,"claim":"Dissected multiple homo-oligomerization determinants (C-terminal coiled-coil, Cys632 disulfide) and separated complex assembly from intrinsic ER Ca2+-release function.","evidence":"Mutagenesis, co-IP, non-reducing SDS-PAGE, electrophysiology, and zebrafish phenotyping","pmids":["20168298","21474446"],"confidence":"High","gaps":["Hierarchy of the three oligomerization domains in native assembly unclear","How disulfide formation is regulated unknown"]},{"year":2013,"claim":"Expanded the channel repertoire by showing TRPP2 forms functionally distinct heteromers with TRPC1, TRPV4, and TRPM3, accounting for diverse native channel properties.","evidence":"Co-IP, AFM, FRET, and single-channel electrophysiology across cell types (consolidated 2008-2014 plus ciliary studies)","pmids":["18323855","19193631","20682256","23977387","25114176","30883612"],"confidence":"High","gaps":["Tissue-specific partner selection rules not defined","In vivo contribution of each heteromer not fully separated"]},{"year":2016,"claim":"Characterized the native ciliary TRPP2-dependent channel and key pore residues, defining its permeation and gating properties directly in cilia.","evidence":"Direct ciliary patch-clamp, CRISPR/Cas9 knockout, and structure-guided pore mutagenesis (D643, S4-S5 linker)","pmids":["27760766","27071085"],"confidence":"High","gaps":["Physiological activating stimulus of the ciliary channel debated","Coupling between ciliary Ca2+ and downstream effectors incompletely mapped"]},{"year":2018,"claim":"Provided atomic-level architecture of the human PKD1-PKD2 complex, revealing a noncanonical TRP fold and features that may restrict cation permeation.","evidence":"Cryo-EM of the PKD1-PKD2 complex at 3.6 Å","pmids":["30093605"],"confidence":"High","gaps":["Structure captured a closed/non-conducting state","Mechanism of physiological gating not visualized"]},{"year":2018,"claim":"Defined PKD2's role in vascular control, showing pressure- and adrenoceptor-activated smooth muscle channels and SUMO-regulated surface trafficking set blood pressure.","evidence":"Inducible cell-specific Pkd2 knockout mice, SUMO assays, patch-clamp, pressure myography, and blood pressure telemetry","pmids":["30511640","31822608"],"confidence":"High","gaps":["SUMO ligase/protease acting on PKD2 not identified","Relationship between vascular and renal functions in ADPKD unresolved"]},{"year":2020,"claim":"Identified the activating ligand for the polycystin channel and an endothelial signaling output, linking complex gating to vasodilation.","evidence":"PC-1/PC-2 reconstitution with the soluble PC-1 N-terminal fragment agonist; EC-specific Pkd2 knockout with eNOS phosphorylation and blood pressure readouts","pmids":["33164752","32364494"],"confidence":"High","gaps":["Physiological trigger for autoproteolytic fragment release unclear","Generality of the agonist across compartments not established"]},{"year":2020,"claim":"Connected TRPP2 Ca2+ channel activity to autophagy through a Ca2+-dependent BECN1 interaction, extending its function beyond ion conduction.","evidence":"Co-IP, CC1/D509V channel-dead mutagenesis, autophagy assays, and BAPTA-AM Ca2+ chelation","pmids":["32543276"],"confidence":"Medium","gaps":["Compartment where the PKD2-BECN1 complex forms not pinpointed","Relevance to cyst pathology not tested in vivo"]},{"year":null,"claim":"How the multiple PKD2 channel assemblies and compartmental functions are coordinated in vivo, and which is the disease-relevant conductance driving cystogenesis, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking ER, plasma-membrane, and ciliary PKD2 functions to cyst initiation","Physiological gating stimulus for the native polycystin complex not defined","Partner-selection logic across tissues unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[29,30,35,40]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[23,40]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,12]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,9,23]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[11,19,30,38]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,34,39]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[36]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[19,27]}],"complexes":["PKD1-PKD2 (polycystin) complex","TRPP2-TRPC1 channel","TRPP2-TRPV4 channel","TRPP2-TRPM3 ciliary channel"],"partners":["PKD1","TRPC1","TRPV4","TRPM3","PKD1L1","BECN1","PRKCSH","EGFR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13563","full_name":"Polycystin-2","aliases":["Autosomal dominant polycystic kidney disease type II protein","Polycystic kidney disease 2 protein","Polycystwin","R48321","Transient receptor potential cation channel subfamily P member 2"],"length_aa":968,"mass_kda":109.7,"function":"Forms a nonselective cation channel (PubMed:11854751, PubMed:11991947, PubMed:15692563, PubMed:26269590, PubMed:27071085, PubMed:31441214, PubMed:39009345). Can function as a homotetrameric ion channel or can form heteromer with PKD1 (PubMed:31441214, PubMed:33164752). Displays distinct function depending on its subcellular localization and regulation by its binding partners (PubMed:11854751, PubMed:11991947, PubMed:27214281, PubMed:29899465). In primary cilium functions as a cation channel, with a preference for monovalent cations over divalent cations that allows K(+), Na(+) and Ca(2+) influx, with low selectivity for Ca(2+) (PubMed:27071085). Involved in fluid-flow mechanosensation by the primary cilium in renal epithelium (By similarity). In the endoplasmic reticulum, likely functions as a K(+) channel to facilitate Ca(2+) release (By similarity). The heterotetrameric PKD1/PKD2 channel has higher Ca(2+) permeability than homomeric PKD2 channel and acts as a primarily Ca(2+)-permeable channel (PubMed:31441214). Interacts with and acts as a regulator of a number of other channels, such as TRPV4, TRPC1, IP3R, RYR2, ultimately further affecting intracellular signaling, to modulate intracellular Ca(2+) signaling (PubMed:11854751, PubMed:11991947, PubMed:27214281, PubMed:29899465). Together with TRPV4, forms mechano- and thermosensitive channels in cilium (PubMed:18695040). In cardiomyocytes, PKD2 modulates Ca(2+) release from stimulated RYR2 receptors through direct association (By similarity). Also involved in left-right axis specification via its role in sensing nodal flow; forms a complex with PKD1L1 in cilia to facilitate flow detection in left-right patterning (By similarity). Acts as a regulator of cilium length together with PKD1 (By similarity). Mediates systemic blood pressure and contributes to the myogenic response in cerebral arteries though vasoconstriction (By similarity)","subcellular_location":"Cell projection, cilium membrane; Endoplasmic reticulum membrane; Cell membrane; Basolateral cell membrane; Cytoplasmic vesicle membrane; Golgi apparatus; Vesicle; Secreted, extracellular exosome","url":"https://www.uniprot.org/uniprotkb/Q13563/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PKD2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PKD2","total_profiled":1310},"omim":[{"mim_id":"620056","title":"POLYCYSTIC KIDNEY DISEASE 7; PKD7","url":"https://www.omim.org/entry/620056"},{"mim_id":"618515","title":"TRANSMEMBRANE PROTEIN 33; TMEM33","url":"https://www.omim.org/entry/618515"},{"mim_id":"618289","title":"ENDOSOME-ASSOCIATED TRAFFICKING REGULATOR 1; ENTR1","url":"https://www.omim.org/entry/618289"},{"mim_id":"618066","title":"HOMEOBOX B CLUSTER ANTISENSE RNA 1, NONCODING; HOXBAS1","url":"https://www.omim.org/entry/618066"},{"mim_id":"617610","title":"POLYCYSTIC KIDNEY DISEASE 5; PKD5","url":"https://www.omim.org/entry/617610"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"blood vessel","ntpm":106.7}],"url":"https://www.proteinatlas.org/search/PKD2"},"hgnc":{"alias_symbol":["PKD4","PC2","Pc-2","TRPP2"],"prev_symbol":[]},"alphafold":{"accession":"Q13563","domains":[{"cath_id":"1.20.120,1.20.120","chopping":"213-242_471-577","consensus_level":"high","plddt":88.5115,"start":213,"end":577},{"cath_id":"-","chopping":"247-458","consensus_level":"high","plddt":91.0614,"start":247,"end":458},{"cath_id":"1.10.287,1.10.287","chopping":"584-693","consensus_level":"high","plddt":92.8334,"start":584,"end":693},{"cath_id":"1.10.238.10","chopping":"704-778","consensus_level":"medium","plddt":64.6349,"start":704,"end":778}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13563","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13563-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13563-F1-predicted_aligned_error_v6.png","plddt_mean":70.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PKD2","jax_strain_url":"https://www.jax.org/strain/search?query=PKD2"},"sequence":{"accession":"Q13563","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13563.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13563/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13563"}},"corpus_meta":[{"pmid":"8650545","id":"PMC_8650545","title":"PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein.","date":"1996","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/8650545","citation_count":1178,"is_preprint":false},{"pmid":"10023895","id":"PMC_10023895","title":"Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group.","date":"1999","source":"Lancet (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/10023895","citation_count":448,"is_preprint":false},{"pmid":"9568711","id":"PMC_9568711","title":"Somatic inactivation of Pkd2 results in polycystic kidney disease.","date":"1998","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9568711","citation_count":446,"is_preprint":false},{"pmid":"9192675","id":"PMC_9192675","title":"Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9192675","citation_count":426,"is_preprint":false},{"pmid":"10497221","id":"PMC_10497221","title":"Identification and characterization of polycystin-2, the PKD2 gene product.","date":"1999","source":"The Journal of biological 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protein with six transmembrane spans, intracellular amino- and carboxyl-termini, similarity to voltage-activated calcium channels, and a potential calcium-binding domain.\",\n      \"method\": \"Positional cloning, sequence analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — original positional cloning with sequence characterization, foundational paper replicated across the field\",\n      \"pmids\": [\"8650545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"PKD1 and PKD2 proteins interact through their C-terminal cytoplasmic tails; the PKD2 C-terminal cytoplasmic tail forms homodimers through a coiled-coil domain distinct from the PKD1 interaction region; PKD1-PKD2 interaction upregulates PKD1 expression.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro binding\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and yeast two-hybrid, independently replicated in multiple subsequent studies\",\n      \"pmids\": [\"9192675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Somatic inactivation (loss of both alleles) of Pkd2 is necessary and sufficient for renal cyst formation in mice, establishing a cellular recessive (two-hit) mechanism for ADPKD type 2.\",\n      \"method\": \"Mouse genetics — unstable allele with intragenic homologous recombination, immunohistochemistry for Pkd2 expression in cysts\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse knockout model with loss-of-function phenotype and protein expression validation, broadly replicated\",\n      \"pmids\": [\"9568711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Polycystin-2 is an ~110-kDa integral membrane glycoprotein that localizes predominantly to the endoplasmic reticulum in native tissues and cultured cells. A 34-amino acid region (Glu787–Ser820) in the C-terminal tail is responsible for exclusive ER retention and mediates interaction with an unidentified ER-binding partner; truncation at or before Glu787 allows plasma membrane trafficking.\",\n      \"method\": \"Immunofluorescence, co-localization with PDI/calnexin, subcellular fractionation, Endo H sensitivity, cell-surface biotinylation, truncation mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (fractionation, Endo H, biotinylation, mutagenesis) in a single rigorous study\",\n      \"pmids\": [\"10497221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PKD2 protein directly associates with TRPC1 (but not TRPC3) via two distinct domains: a 73-amino acid region in the C-terminal cytoplasmic tail and a more N-terminal domain within transmembrane segments S2–S5 including the putative pore region.\",\n      \"method\": \"Co-immunoprecipitation in transfected cells and in vitro binding assay, deletion mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP in cells plus in vitro binding, single lab, two orthogonal methods\",\n      \"pmids\": [\"10097141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PKD2 interacts with Hax-1 (a protein associated with the actin cytoskeleton) via its C-terminal domain, and Hax-1 associates with the F-actin-binding protein cortactin, providing a molecular link between PKD2 and the actin cytoskeleton. PKD2 and Hax-1 co-localize in the cell body and in cellular processes/lamellipodia.\",\n      \"method\": \"Yeast two-hybrid screen, immunofluorescence co-localization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid plus co-localization, no reciprocal Co-IP or functional validation of interaction in mammalian cells\",\n      \"pmids\": [\"10760273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Polycystin-2 localizes to the basolateral plasma membrane of kidney tubular epithelial cells in vivo, distinct from the junctional localization of polycystin-1, suggesting independent as well as overlapping functions.\",\n      \"method\": \"Immunohistochemistry and immunofluorescence microscopy of human and murine renal tissues\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunofluorescence and IHC in native tissues, single lab, two tissue preparation methods\",\n      \"pmids\": [\"10770959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PKD2 interacts with mDia1 (a RhoA GTPase-binding formin) via the PKD2 C-terminus binding to the mDia1 N-terminus. This interaction localizes PKD2 to mitotic spindles in dividing cells; RNAi knockdown of mDia1 causes loss of PKD2 from spindles and alters intracellular Ca2+ release.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in native and transfected cells, immunofluorescence, RNAi knockdown, Ca2+ imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP in native cells plus RNAi functional validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"15123714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PKD2 (TRPP2) subcellular localization and trafficking are regulated by phosphofurin acidic cluster sorting proteins PACS-1 and PACS-2, which bind an acidic cluster in the PKD2 C-terminal domain. This binding is regulated by casein kinase 2-mediated phosphorylation (at Ser812), directing PKD2 routing between ER, Golgi, and plasma membrane.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, subcellular fractionation, mutagenesis (Ser812Ala), functional electrophysiology\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution of phosphorylation-dependent binding with mutagenesis plus functional channel assays, multiple orthogonal methods\",\n      \"pmids\": [\"15692563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PKD2 functions as an EGF-activated plasma membrane cation channel. EGF activates PKD2 via PLC and PI3K signaling, independently of store depletion. PIP2 negatively regulates PKD2 channel activity. PKD2 physically interacts with PLC-γ2 and EGFR and co-localizes with EGFR and PIP2 in the primary cilium.\",\n      \"method\": \"Electrophysiology (whole-cell patch clamp), RNAi knockdown, PIP2/PIP3 pipette infusion, pharmacology, co-immunoprecipitation, immunofluorescence\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods including electrophysiology, RNAi, biochemical interaction, and pharmacology in a single study\",\n      \"pmids\": [\"16135816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Chlamydomonas reinhardtii, CrPKD2 moves bidirectionally in the flagellar membrane and its flagellar entry and abundance require intraflagellar transport (IFT). Flagellar CrPKD2 increases fourfold during gametogenesis, and RNAi strains show defects in flagella-dependent mating, indicating PKD2 couples flagellar adhesion to Ca2+ signaling during mating.\",\n      \"method\": \"GFP live imaging, FRAP, IFT block experiments, RNAi, mating assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live imaging and FRAP with functional RNAi validation, ortholog study in Chlamydomonas\",\n      \"pmids\": [\"17984324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRPP2 and TRPC1 assemble to form a heteromeric receptor-operated channel with a 2:2 stoichiometry and alternating subunit arrangement, exhibiting unique single-channel conductance, amiloride sensitivity, and ion permeability profiles distinct from either subunit alone. Endogenous TRPP2/TRPC1 activity occurs in kidney cells and both subunits co-localize at the primary cilium.\",\n      \"method\": \"Electrophysiology, co-immunoprecipitation from kidney membranes, gain/loss-of-function experiments, immunofluorescence, atomic force microscopy\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (electrophysiology, AFM structural analysis, Co-IP from native tissue, gain/loss-of-function), replicated across papers\",\n      \"pmids\": [\"18323855\", \"19850920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ER-localized TRPP2 reduces the Ca2+ concentration in the ER by increasing ER Ca2+ permeability, thereby counteracting SERCA activity and reducing IP3R-mediated Ca2+ release. This protects cells from apoptosis; TRPP2 knockdown in renal epithelial cells increases ER Ca2+ release and augments apoptotic sensitivity.\",\n      \"method\": \"Ca2+ imaging, RNAi knockdown, apoptosis assays, pharmacology (thapsigargin, IP3R agonists)\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional Ca2+ measurements with RNAi knockdown and pharmacological validation, single lab\",\n      \"pmids\": [\"19153608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The TRPP2/PKD1 complex contains 3 TRPP2 and 1 PKD1 subunits. A newly identified coiled-coil domain in the TRPP2 C-terminus forms a homotrimer (confirmed by crystallography) that binds a single PKD1 C-terminal coiled-coil. Mutations disrupting the TRPP2 coiled-coil trimer abolish complex assembly and reduce surface expression of both proteins.\",\n      \"method\": \"Biochemistry, X-ray crystallography, single-molecule subunit counting in live cells (fluorescence), mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus single-molecule counting and mutagenesis functional validation in one study\",\n      \"pmids\": [\"19556541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PKD2/TRPP2 forms homotetramers and heteromeric complexes with TRPC1 in a tetrameric configuration. In homomeric PC2 channels, four subconductance states follow staircase behavior that is pH- and voltage-dependent; low pH inhibits homomeric but not heteromeric PC2/TRPC1 complexes, demonstrating distinct functional properties between homo- and heteromeric assemblies.\",\n      \"method\": \"Single-channel electrophysiology, atomic force microscopy, kinetic analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — electrophysiology plus AFM structural analysis, single lab\",\n      \"pmids\": [\"19193631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A coiled-coil domain in the PKD2 C-terminus functions as an essential homodimerization domain required for PC1 binding but not for PKD2 self-oligomerization. Dimerization-defective PKD2 mutants cannot reconstitute PC1/PC2 complexes at the plasma membrane or ER-PM junctions but retain ER Ca2+-release channel function. Expression of these mutants in zebrafish produces cystic phenotype.\",\n      \"method\": \"Mutagenesis, co-immunoprecipitation, electrophysiology, zebrafish in vivo rescue\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis with biochemical, electrophysiological, and in vivo validation across multiple orthogonal methods\",\n      \"pmids\": [\"20168298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRPP2 interacts with TRPV4 (but not TRPA1 or TRPM8), forming a heterotetramer with 2:2 stoichiometry and alternating subunit arrangement, analogous to the TRPP2-TRPC1 heteromer.\",\n      \"method\": \"Co-immunoprecipitation, atomic force microscopy with antibody labeling\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus AFM structural analysis, single lab, two orthogonal methods\",\n      \"pmids\": [\"20682256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Protein kinase D phosphorylates polycystin-2 at Ser801 in the C-terminus; this phosphorylation is stimulated by serum/EGF, is required for PKD2-mediated inhibition of cell proliferation, and for ATP-stimulated ER Ca2+ release. A pathogenic ADPKD mutation (S804N) abolishes Ser801 phosphorylation.\",\n      \"method\": \"Mutagenesis, in vitro kinase assay, Ca2+ imaging, cell proliferation assay, Western blot\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and functional validation, single lab\",\n      \"pmids\": [\"20881056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PRKCSH binds the C-terminal domain of TRPP2 in the ER and inhibits HERP-mediated ubiquitination of TRPP2, protecting it from ER-associated degradation. Loss of PRKCSH leads to reduced TRPP2 levels and cyst formation in zebrafish.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, zebrafish knockdown/rescue experiments\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with ubiquitination assay and in vivo zebrafish validation, single lab\",\n      \"pmids\": [\"19801576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Pkd1l1 physically interacts with Pkd2 and both co-localize to cilia of the embryonic node. Pkd1l1 and Pkd2 point mutants phenocopy each other (right isomerism, failure to activate asymmetric gene expression), establishing Pkd1l1 as a Pkd2 binding partner required for L-R patterning downstream of nodal flow.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization in node cilia, genetic epistasis (parallel mutant phenotyping)\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP plus in vivo genetic epistasis replicated in two independent studies (mouse and medaka)\",\n      \"pmids\": [\"21307093\", \"21307098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The TRPP2/PKD1 C-terminal coiled-coil complex forms a novel di-trimer configuration (upstream trimer of three TRPP2 helices; downstream trimer of two TRPP2 and one PKD1 helix). Mutagenesis of critical interface positions abolishes heteromeric coiled-coil complex assembly in full-length proteins in cells.\",\n      \"method\": \"Computational docking based on crystal structure of TRPP2 coiled-coil trimer, mutagenesis, biochemical co-immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure-based computational model validated by mutagenesis and biochemistry, single lab\",\n      \"pmids\": [\"21642537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cys632 in the PKD2 extracellular loop constitutes a third homodimerization domain via disulfide bond formation. Combined disruption of Cys632 and the C-terminal coiled-coil domain nearly abolishes homodimer formation and ER Ca2+ release, but C632A mutant retains ability to heterodimerize with PKD1.\",\n      \"method\": \"Mutagenesis, non-reducing SDS-PAGE, co-immunoprecipitation, Ca2+ imaging (ATP-stimulated ER Ca2+ release)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with biochemical and functional Ca2+ validation, single lab\",\n      \"pmids\": [\"21474446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRPP2 and TRPV4 assemble to form a 23-pS divalent cation-permeable non-selective ion channel at the apical membrane of renal collecting duct principal cells. This channel is activated by EGF via EGFR tyrosine kinase signaling; loss of either subunit reduces the 23-pS channel activity.\",\n      \"method\": \"Patch-clamp electrophysiology, immunofluorescence, co-immunoprecipitation, shRNA knockdown\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — patch-clamp electrophysiology with Co-IP and RNAi, single lab\",\n      \"pmids\": [\"23977387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRPP2 is expressed in cerebral artery smooth muscle cells, residing primarily (~88%) in the plasma membrane. TRPP2 mediates stretch-activated cation currents (ICat), and its knockdown reduces myogenic tone at intravascular pressures of 40–100 mmHg without altering depolarization-induced vasoconstriction.\",\n      \"method\": \"Arterial biotinylation, immunofluorescence, patch-clamp electrophysiology, RNAi knockdown, pressure myography\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (biotinylation, electrophysiology, RNAi, myography), single lab\",\n      \"pmids\": [\"23858011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRPV4, TRPC1, and TRPP2 assemble to form a heteromeric channel complex; all three subunits contribute to the ion permeation pore. This heteromeric channel mediates flow-induced Ca2+ influx in native vascular endothelial cells.\",\n      \"method\": \"Two-step co-immunoprecipitation, FRET, patch-clamp electrophysiology with pore-dead mutants, Ca2+ imaging\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two-step Co-IP plus FRET plus functional electrophysiology with pore-dead mutants, single lab\",\n      \"pmids\": [\"25114176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Native TRPP2 is N-glycosylated at five asparagines in the first extracellular loop. Glycosylation is required for efficient TRPP2 biogenesis; mutation of glycosylated asparagines severely reduces protein expression. Glucosidase II (GIIβ/PRKCSH) mediates glycan trimming of TRPP2, and impaired trimming reduces TRPP2 abundance.\",\n      \"method\": \"Mass spectrometry, mutagenesis, Western blot, pharmacological inhibition of lysosomal degradation, genetic (Prkcsh-/- mice)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mass spectrometry identification plus mutagenesis and genetic validation in knockout mice, multiple orthogonal methods\",\n      \"pmids\": [\"24719335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Trpp2 (together with Trpv4) mediates endocardial calcium responses to oscillatory flow and is required for klf2a mechanosensitive expression and heart valve morphogenesis in zebrafish. Absence of Trpp2 leads to valve defects.\",\n      \"method\": \"Live Ca2+ imaging, klf2a promoter reporter assay, morpholino knockdown in zebrafish, mathematical flow modeling\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging with Ca2+ reporter and promoter assay plus in vivo knockdown, single lab\",\n      \"pmids\": [\"25959969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Pkd2 localizes to primary cilia of radial glia cells (RGCs) in the brain ventricular epithelium; conditional ablation of Pkd2 disrupts planar cell polarity (PCP) development in RGCs and ependymal cells and impairs asymmetric localization of PCP protein Vangl2, implicating Pkd2 in mechanosensory-driven PCP establishment.\",\n      \"method\": \"Immunofluorescence, conditional Cre-lox knockout (Nestin-Cre;Pkd2flox/flox), double-heterozygous epistasis (Pkd1 × Vangl2)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with genetic epistasis and immunofluorescence, single lab\",\n      \"pmids\": [\"26245976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PKA directly phosphorylates polycystin-2 at Ser829 in the C-terminus; this increases channel mean open time without altering single-channel conductance. The phosphorylation is reversed by alkaline phosphatase. A truncation at Arg742 or mutation S829A abolishes PKA-mediated channel activation.\",\n      \"method\": \"Lipid bilayer reconstitution, in vitro PKA phosphorylation, mutagenesis (S829A, R742X), electrophysiology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with PKA plus mutagenesis and single-channel electrophysiology, rigorous controls\",\n      \"pmids\": [\"26269590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A constitutively active gain-of-function TRPP2 mutant (S4-S5 linker/S5 domain) revealed that extracellular divalent ions (including Ca2+) inhibit monovalent ion permeation by directly blocking the TRPP2 channel pore, and that D643 (a negatively charged pore residue) is crucial for channel permeability.\",\n      \"method\": \"Mutagenesis scanning, electrophysiology, zebrafish rescue experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structure-guided mutagenesis with electrophysiology and in vivo zebrafish validation, multiple methods\",\n      \"pmids\": [\"27071085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The native TRPP2-dependent channel in murine renal primary cilia is a large-conductance cation channel (97–189 pS) permeable to K+, Ca2+, and Na+ with permeability ratios PK:PCa:PNa of 1:0.55:0.14. Open probability increases with membrane depolarization or elevated cytoplasmic Ca2+. CRISPR/Cas9 knockout of TRPP2 eliminates this channel current.\",\n      \"method\": \"Direct electrophysiology from isolated primary cilia, CRISPR/Cas9 gene editing\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct ciliary patch-clamp with CRISPR knockout confirmation, rigorous electrophysiological characterization\",\n      \"pmids\": [\"27760766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The cryo-EM structure of the human PKD1-PKD2 complex at 3.6 Å reveals a 1:3 (PKD1:PKD2) ratio with domain-swapped, noncanonical TRP channel architecture. PKD1 contains a VGIC fold; its S6 helix is broken into S6a (resembling pore helix 1) and S6b (with three positively charged cavity-facing residues that may block cation permeation). Additional resolved domains include a five-TM helix domain and a cytosolic PLAT domain in PKD1.\",\n      \"method\": \"Cryo-electron microscopy at 3.6 Å resolution\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure providing direct atomic-level insight into complex architecture\",\n      \"pmids\": [\"30093605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PKD2 channels in arterial smooth muscle cells are modified by SUMO1 at physiological intravascular pressures. SUMOylated PKD2 (SUMO-PKD2) recycles between intracellular compartments and the plasma membrane, while unmodified PKD2 is surface-resident. Intravascular pressure activates voltage-dependent Ca2+ influx that stimulates SUMO-PKD2 recycling to the surface; desumoylation eliminates pressure-activated INa and causes vasodilation.\",\n      \"method\": \"Cell-specific inducible Pkd2 knockout mice, SUMO modification assays, patch-clamp electrophysiology, pressure myography\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible cell-specific KO with biochemical SUMOylation assay, electrophysiology, and functional vascular assays, multiple orthogonal methods\",\n      \"pmids\": [\"31822608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SLC25A25, a Ca2+-regulated mitochondrial ATP-Mg/Pi solute carrier, acts downstream of TRPP2-mediated ciliary Ca2+ signals. Identified by a genome-wide forward genetic screen in Drosophila and validated in zebrafish left-right patterning, establishing an evolutionarily conserved link between TRPP2 ciliary signaling and mitochondrial metabolism.\",\n      \"method\": \"Genome-wide forward genetic screen (Drosophila), zebrafish targeted knockdown with left-right patterning readout\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased genetic screen plus targeted in vivo validation in two organisms, single lab\",\n      \"pmids\": [\"30080851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Intravascular flow activates endothelial PKD2 channels, leading to Ca2+ influx that activates SK/IK channels and eNOS phosphorylation at Ser1176, producing arterial hyperpolarization and vasodilation. EC-specific Pkd2 knockout elevates blood pressure without altering cardiac function or kidney anatomy.\",\n      \"method\": \"Inducible EC-specific Pkd2 knockout mice, patch-clamp electrophysiology, eNOS phosphorylation assay, pressure myography, blood pressure telemetry\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible EC-specific KO with electrophysiology, signaling assays, and in vivo blood pressure measurement, multiple orthogonal methods\",\n      \"pmids\": [\"32364494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The heteromeric PC-1/PC-2 polycystin complex reconstituted in the plasma membrane functions as an outwardly rectifying channel. A soluble fragment generated from autoproteolytic cleavage of the PC-1 N-terminal extracellular domain acts as an intrinsic agonist that is necessary and sufficient for channel activation of both reconstituted and native ciliary polycystin channels.\",\n      \"method\": \"Reconstitution of PC-1/PC-2 complex in mammalian plasma membrane, electrophysiology, application of soluble PC-1 N-terminal fragment, ciliary patch-clamp\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional reconstitution plus ciliary electrophysiology with defined agonist, multiple orthogonal approaches\",\n      \"pmids\": [\"33164752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PKD2 forms a protein complex with BECN1 (beclin-1) via the CC1 coiled-coil domain in the PKD2 C-terminus, inducing autophagy. This interaction depends on PKD2 Ca2+ channel activity; a channel-dead mutant (D509V) shows diminished BECN1 binding and fails to induce autophagy. Depletion of intracellular Ca2+ (BAPTA-AM) disrupts the PKD2-BECN1 complex and blocks starvation-induced autophagy.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis (CC1 deletion, D509V), autophagy assays (LC3 II/I, autophagosomes), BAPTA-AM Ca2+ chelation\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis and functional autophagy validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32543276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Chlamydomonas PKD2 targets and anchors mastigonemes (MST1 glycoprotein filamentous polymers) to the extracellular surface of cilia. PKD2-mastigoneme complexes connect to axonemal doublets 4 and 8; pkd2 mutant cilia lack mastigonemes and cells swim with reduced velocity, suggesting a mechanosensory role.\",\n      \"method\": \"Immunofluorescence, electron microscopy, genetic analysis of pkd2 mutants, motility assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct structural imaging plus genetic loss-of-function with functional readout, single lab in Chlamydomonas ortholog\",\n      \"pmids\": [\"32348466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The large-conductance TRPP2-dependent channel in renal primary cilia also requires TRPM3; pharmacological activation with the TRPM3 agonist pregnenolone sulfate greatly enhances channel activity, and the specific TRPM3 inhibitor isosakuranetin blocks the channel. CRISPR/Cas9 knockout of TRPM3 eliminates the ciliary channel without altering ciliary TRPP2 protein levels.\",\n      \"method\": \"Direct ciliary electrophysiology, pharmacology (pregnenolone sulfate, isosakuranetin), CRISPR/Cas9 knockout of TRPM3, Western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiology with pharmacology and genetic CRISPR knockout, single lab\",\n      \"pmids\": [\"30883612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PKD2 channels in arterial smooth muscle cells are activated by intravascular pressure and α1-adrenoceptors, mediating an inward Na+ current that causes membrane depolarization and vasoconstriction. Inducible smooth muscle-specific PKD2 knockout lowers physiological blood pressure, reduces hypertension, and prevents pathological arterial remodeling.\",\n      \"method\": \"Inducible smooth muscle-specific Pkd2 knockout mice, patch-clamp electrophysiology, pressure myography, blood pressure telemetry\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible cell-type-specific KO with electrophysiology and in vivo blood pressure/vascular phenotyping, multiple orthogonal methods\",\n      \"pmids\": [\"30511640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Fission yeast Pkd2 (polycystin homolog) permeates calcium when the membrane is stretched. In vitro reconstitution in giant unilamellar vesicles demonstrated Ca2+ permeability upon hypoosmotic shock; in vivo, pkd2 temperature-sensitive and hypomorphic mutants reduced intracellular Ca2+ levels and diminished cytokinesis-associated Ca2+ spikes, establishing Pkd2 as a mechanosensitive Ca2+-permeable channel activated by membrane stretching.\",\n      \"method\": \"Cell-free expression/reconstitution in GUVs, Ca2+ imaging in mutant yeast cells, hypoosmotic shock experiments\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution plus in vivo genetic validation, single lab, ortholog study in fission yeast\",\n      \"pmids\": [\"36200871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The subcellular localization of TRPP2 determines its function: ER-localized TRPP2 (Ser812Asp, PACS-trapped) more effectively rescues left-right asymmetry defects in TRPP2-deficient zebrafish, while plasma membrane-directed TRPP2 (Ser812Ala) rescues cyst formation. This indicates that TRPP2 assumes distinct compartment-specific roles.\",\n      \"method\": \"PACS-binding mutagenesis (Ser812Ala, Ser812Asp), zebrafish knockdown/rescue experiments, immunofluorescence\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with in vivo zebrafish rescue using distinct functional readouts, single lab\",\n      \"pmids\": [\"18417723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Drosophila Pkd2 is required for directional sperm movement inside the female reproductive tract. Targeted disruption causes male sterility without affecting spermatogenesis; mutant sperm are motile but fail to enter female storage organs, demonstrating PKD2 cation channel function in sperm flagella for directed movement.\",\n      \"method\": \"Genetic disruption (targeted P-element excision), fertility assays, sperm motility analysis, immunolocalization\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with specific behavioral/cellular phenotype in Drosophila ortholog, single lab\",\n      \"pmids\": [\"14680633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Drosophila Pkd2 loss-of-function severely reduces visceral smooth muscle contractility, which is rescued by muscle-specific Pkd2 expression. Pkd2 genetically interacts with the ryanodine receptor to regulate skeletal muscle Ca2+ oscillation during excitation-contraction coupling; Pkd2 is haploinsufficient for normal smooth muscle contractility.\",\n      \"method\": \"Genetic loss-of-function, tissue-specific rescue (Gal4/UAS), pharmacological perturbation (ryanodine), genetic interaction analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis and tissue-specific rescue with functional readout, single lab in Drosophila ortholog\",\n      \"pmids\": [\"14732716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Conditional loss of Pkd2 causes beta-catenin upregulation, as well as increased axin2 and cMyc expression, in renal collecting duct cells. Pkd2-null immortalized collecting duct cells show aberrant cell-cell contact, ciliogenesis, and tubulomorphogenesis, linking PC2 loss to dysregulation of beta-catenin-dependent signaling.\",\n      \"method\": \"Cre-loxP conditional knockout, Western blot, immunofluorescence, tubulomorphogenesis assay\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with defined molecular and cellular phenotypes, single lab\",\n      \"pmids\": [\"19939939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Polycystin-2 (TRPP2) channel activity in human syncytiotrophoblast apical membranes is rapidly and completely inhibited by reactive oxygen species (H2O2, tBHP) applied to the intracellular side (IC50 ~131 nM in native membranes), with inhibition mediated by targeting both membrane lipids (lipid peroxidation) and the channel protein itself.\",\n      \"method\": \"Lipid bilayer reconstitution, electrophysiology, TBARS measurement, catalase treatment\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiology in reconstituted native membranes with dose-response, single lab\",\n      \"pmids\": [\"18417208\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PKD2 encodes polycystin-2 (TRPP2), a Ca2+-permeable nonselective cation channel with six transmembrane domains that forms a 1:3 heteromeric receptor/ion channel complex with PKD1 (resolved by cryo-EM at 3.6 Å), and also assembles into homotetramers and heteromeric channels with TRPC1, TRPV4, and TRPM3. Its subcellular localization—ER, plasma membrane, or primary cilium—is regulated by CK2-mediated phosphorylation of Ser812 and PACS adaptor protein binding, with compartment-specific functions: at the ER it modulates luminal Ca2+ to regulate apoptosis and autophagy (via BECN1 interaction); at the plasma membrane it mediates mechanosensitive cation currents activated by flow, pressure, or EGF/PLC/PI3K signaling (negatively regulated by PIP2) to control vascular tone, blood pressure, and endothelial eNOS activation; and in primary cilia it forms a large-conductance (TRPM3-containing) channel required for mechanosensation and left-right axis determination (through interaction with Pkd1l1). SUMO1 modification of PKD2 in arterial myocytes regulates its surface density and pressure-dependent activation, while N-glycosylation at five extracellular asparagines and glycan trimming by GII/PRKCSH control its biogenesis and stability. Somatic biallelic inactivation of PKD2 in renal tubular cells is necessary and sufficient for cyst formation, establishing a cellular recessive two-hit mechanism for ADPKD.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PKD2 encodes polycystin-2 (TRPP2), a Ca2+-permeable nonselective cation channel with six transmembrane spans and intracellular N- and C-termini that operates across multiple cellular compartments to transduce mechanical and chemical signals into Ca2+ flux [#0, #29]. Its defining partnership is with PKD1 (polycystin-1): the two associate through C-terminal coiled-coil interactions, with the TRPP2 C-terminus forming a homotrimer that binds a single PKD1 coiled-coil to build a 1:3 (PKD1:TRPP2) complex, an arrangement resolved by cryo-EM as a domain-swapped, noncanonical TRP architecture [#1, #13, #31]. Channel assembly is further organized by a Cys632 extracellular disulfide and the C-terminal coiled-coil, and disrupting these abolishes homodimerization and complex formation [#15, #21]. Beyond PKD1, TRPP2 assembles into homotetramers and heteromeric channels with TRPC1, TRPV4, and TRPM3, each with distinct conductance and permeation properties, and these complexes mediate flow-induced Ca2+ influx in endothelium and ciliary mechanosensation [#11, #14, #16, #24, #38]. TRPP2 localization—ER, basolateral plasma membrane, or primary cilium—is set by a C-terminal acidic-cluster signal whose CK2-dependent phosphorylation at Ser812 controls PACS adaptor binding and routing, and these compartments correspond to distinct functions: ER-localized TRPP2 lowers luminal Ca2+ to limit IP3R-mediated release and apoptosis and binds BECN1 to drive autophagy, while plasma-membrane channels carry mechanosensitive and EGF/PLC/PI3K-activated cation currents [#3, #8, #9, #12, #36, #41]. Channel gating is tuned by PKA, PKD, and CK2 phosphorylation of the C-terminus and by SUMO1 modification that controls surface density in arterial myocytes [#17, #28, #32], and biogenesis depends on N-glycosylation and PRKCSH/glucosidase-II-mediated glycan trimming that protect TRPP2 from ER-associated degradation [#18, #25]. In vascular smooth muscle and endothelium, pressure- and flow-activated PKD2 channels control myogenic tone, eNOS-dependent vasodilation, and blood pressure [#34, #39], and in cilia the TRPP2-dependent channel directs left-right axis determination through Pkd1l1 [#19]. Somatic biallelic inactivation of Pkd2 in renal tubular cells is necessary and sufficient for cyst formation, establishing a cellular recessive two-hit mechanism for autosomal dominant polycystic kidney disease [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the molecular identity of PKD2 as a membrane protein, framing it as a candidate channel rather than an unknown disease gene.\",\n      \"evidence\": \"Positional cloning and sequence analysis revealing six transmembrane spans and similarity to voltage-gated Ca2+ channels\",\n      \"pmids\": [\"8650545\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sequence prediction alone did not demonstrate channel activity\", \"No subcellular localization or partner identified\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined the central PKD1-PKD2 partnership and the C-terminal coiled-coil that mediates it, explaining why mutations in either gene cause the same disease.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, and in vitro binding mapping the interacting C-terminal tails\",\n      \"pmids\": [\"9192675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the complex not resolved\", \"Functional consequence for channel activity not tested\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated the cellular genetic basis of ADPKD, showing cyst formation follows a recessive two-hit loss of Pkd2 within tubular cells.\",\n      \"evidence\": \"Mouse unstable-allele genetics with intragenic recombination and Pkd2 immunohistochemistry in cysts\",\n      \"pmids\": [\"9568711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling driving cyst growth not defined\", \"Cell-of-origin timing not addressed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Localized polycystin-2 predominantly to the ER and identified the C-terminal retention signal, raising the question of how it reaches the plasma membrane and cilium.\",\n      \"evidence\": \"Immunofluorescence, fractionation, Endo H sensitivity, biotinylation, and truncation mutagenesis\",\n      \"pmids\": [\"10497221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the ER-binding partner unresolved at this stage\", \"Mechanism of regulated export not known\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that compartmental routing is actively regulated by CK2 phosphorylation of Ser812 and PACS adaptor binding, providing a switch between ER, Golgi, and plasma membrane pools.\",\n      \"evidence\": \"Co-IP, phosphorylation assays, Ser812Ala mutagenesis, fractionation, and electrophysiology\",\n      \"pmids\": [\"15692563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling CK2 activity on PKD2 not defined\", \"How routing couples to physiological demand unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked subcellular localization to distinct physiological outputs, showing ER-trapped versus plasma-membrane TRPP2 rescue different defects.\",\n      \"evidence\": \"Ser812Ala/Ser812Asp mutagenesis with zebrafish rescue of left-right asymmetry versus cyst phenotypes\",\n      \"pmids\": [\"18417723\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular effectors at each compartment not fully mapped\", \"Quantitative partitioning between pools in native cells unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved the architecture of the PKD1-PKD2 complex as a 3:1 trimer-of-TRPP2 binding one PKD1, defining the assembly rule for the complex.\",\n      \"evidence\": \"Crystallography of the TRPP2 C-terminal coiled-coil, single-molecule subunit counting, and mutagenesis\",\n      \"pmids\": [\"19556541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full transmembrane architecture not resolved at this stage\", \"Gating mechanism of the assembled complex unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established a direct ER function for TRPP2 in lowering luminal Ca2+ to counteract SERCA and limit apoptotic Ca2+ release.\",\n      \"evidence\": \"Ca2+ imaging, RNAi knockdown, apoptosis assays, and pharmacology in renal epithelial cells\",\n      \"pmids\": [\"19153608\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of TRPP2 as the ER Ca2+ conductance not fully isolated from partners\", \"Relationship to cyst pathology not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Dissected multiple homo-oligomerization determinants (C-terminal coiled-coil, Cys632 disulfide) and separated complex assembly from intrinsic ER Ca2+-release function.\",\n      \"evidence\": \"Mutagenesis, co-IP, non-reducing SDS-PAGE, electrophysiology, and zebrafish phenotyping\",\n      \"pmids\": [\"20168298\", \"21474446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy of the three oligomerization domains in native assembly unclear\", \"How disulfide formation is regulated unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Expanded the channel repertoire by showing TRPP2 forms functionally distinct heteromers with TRPC1, TRPV4, and TRPM3, accounting for diverse native channel properties.\",\n      \"evidence\": \"Co-IP, AFM, FRET, and single-channel electrophysiology across cell types (consolidated 2008-2014 plus ciliary studies)\",\n      \"pmids\": [\"18323855\", \"19193631\", \"20682256\", \"23977387\", \"25114176\", \"30883612\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific partner selection rules not defined\", \"In vivo contribution of each heteromer not fully separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Characterized the native ciliary TRPP2-dependent channel and key pore residues, defining its permeation and gating properties directly in cilia.\",\n      \"evidence\": \"Direct ciliary patch-clamp, CRISPR/Cas9 knockout, and structure-guided pore mutagenesis (D643, S4-S5 linker)\",\n      \"pmids\": [\"27760766\", \"27071085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological activating stimulus of the ciliary channel debated\", \"Coupling between ciliary Ca2+ and downstream effectors incompletely mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided atomic-level architecture of the human PKD1-PKD2 complex, revealing a noncanonical TRP fold and features that may restrict cation permeation.\",\n      \"evidence\": \"Cryo-EM of the PKD1-PKD2 complex at 3.6 Å\",\n      \"pmids\": [\"30093605\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure captured a closed/non-conducting state\", \"Mechanism of physiological gating not visualized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined PKD2's role in vascular control, showing pressure- and adrenoceptor-activated smooth muscle channels and SUMO-regulated surface trafficking set blood pressure.\",\n      \"evidence\": \"Inducible cell-specific Pkd2 knockout mice, SUMO assays, patch-clamp, pressure myography, and blood pressure telemetry\",\n      \"pmids\": [\"30511640\", \"31822608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO ligase/protease acting on PKD2 not identified\", \"Relationship between vascular and renal functions in ADPKD unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified the activating ligand for the polycystin channel and an endothelial signaling output, linking complex gating to vasodilation.\",\n      \"evidence\": \"PC-1/PC-2 reconstitution with the soluble PC-1 N-terminal fragment agonist; EC-specific Pkd2 knockout with eNOS phosphorylation and blood pressure readouts\",\n      \"pmids\": [\"33164752\", \"32364494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological trigger for autoproteolytic fragment release unclear\", \"Generality of the agonist across compartments not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected TRPP2 Ca2+ channel activity to autophagy through a Ca2+-dependent BECN1 interaction, extending its function beyond ion conduction.\",\n      \"evidence\": \"Co-IP, CC1/D509V channel-dead mutagenesis, autophagy assays, and BAPTA-AM Ca2+ chelation\",\n      \"pmids\": [\"32543276\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Compartment where the PKD2-BECN1 complex forms not pinpointed\", \"Relevance to cyst pathology not tested in vivo\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple PKD2 channel assemblies and compartmental functions are coordinated in vivo, and which is the disease-relevant conductance driving cystogenesis, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking ER, plasma-membrane, and ciliary PKD2 functions to cyst initiation\", \"Physiological gating stimulus for the native polycystin complex not defined\", \"Partner-selection logic across tissues unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [29, 30, 35, 40]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [23, 40]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 12]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 9, 23]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [11, 19, 30, 38]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 34, 39]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [36]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [19, 27]}\n    ],\n    \"complexes\": [\n      \"PKD1-PKD2 (polycystin) complex\",\n      \"TRPP2-TRPC1 channel\",\n      \"TRPP2-TRPV4 channel\",\n      \"TRPP2-TRPM3 ciliary channel\"\n    ],\n    \"partners\": [\n      \"PKD1\",\n      \"TRPC1\",\n      \"TRPV4\",\n      \"TRPM3\",\n      \"PKD1L1\",\n      \"BECN1\",\n      \"PRKCSH\",\n      \"EGFR\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}