{"gene":"SEC63","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2000,"finding":"Mammalian SEC63 forms a ribosome-free complex with SEC61 and SEC62 in the ER membrane, representing a post-translational translocation apparatus distinct from the ribosome-bound SEC61 complex used for co-translational import.","method":"Biochemical fractionation, primary sequence homology analysis, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-purification establishing complex membership, replicated across subsequent studies","pmids":["10799540"],"is_preprint":false},{"year":1993,"finding":"Yeast SEC63p (DnaJ homolog) genetically interacts with KAR2/BiP (DnaK homolog) in the ER: temperature-sensitive kar2 and sec63 mutations form synthetic lethals, dominant KAR2 mutations suppress sec63-1 in an allele-specific manner, and sec63-1 induces KAR2 transcription, indicating direct functional cooperation in protein translocation.","method":"Genetic epistasis, suppressor analysis, allele-specific suppression, mRNA Northern blot","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal genetic approaches showing allele-specific interaction, foundational study","pmids":["8305736"],"is_preprint":false},{"year":1993,"finding":"Suppressor screen of sec63-101 in yeast identified SON1-SON5 genes; SON1 encodes a nuclear protein whose loss suppresses sec63 alleles with regional specificity, placing SEC63 in a pathway important for both ER translocation and nuclear protein localization.","method":"Extragenic suppressor screen, genetic complementation, gene cloning and sequencing","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis by suppressor genetics, single lab","pmids":["8514125"],"is_preprint":false},{"year":1993,"finding":"High-copy suppressor screen of sec63-101 identified HSS1/SEC66, an integral ER membrane glycoprotein that physically associates with SEC62p and SEC63p; disruption of HSS1 causes accumulation of translocation precursors, placing HSS1/SEC66 as a functional component of the yeast translocation apparatus.","method":"High-copy suppressor screen, genetic disruption, precursor accumulation assay, complex co-purification","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — suppressor genetics combined with functional translocation assay and complex identification","pmids":["8257794"],"is_preprint":false},{"year":2003,"finding":"In yeast, SEC62p and SEC63p interact directly at their cytosolic surfaces; SEC72p homodimerizes; and YLR301w (novel protein) was identified as an in vivo interacting partner of SEC72p within the SEC62/SEC63 tetrameric complex.","method":"Yeast two-hybrid, co-immunoprecipitation, domain mapping","journal":"Yeast (Chichester, England)","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct interaction between essential subunits confirmed by Y2H and Co-IP, single lab","pmids":["12518317"],"is_preprint":false},{"year":2004,"finding":"Loss-of-function mutations in SEC63, encoding an ER protein translocation component, cause autosomal dominant polycystic liver disease in humans, implicating co-translational ER protein-processing pathways in maintaining biliary epithelial luminal structure.","method":"Human genetic mapping, mutation identification by sequencing, disease association","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — disease-causing mutations defined in multiple families, foundational paper with 195 citations","pmids":["15133510"],"is_preprint":false},{"year":2010,"finding":"Hph1 and Hph2, integral ER membrane proteins, interact with SEC63, SEC62, SEC71, and SEC72 of the yeast SEC63/SEC62 post-translational translocation complex, and loss of Hph1/Hph2 along with the complex impairs biogenesis of vacuolar proton ATPase subunit Vph1.","method":"Split-ubiquitin two-hybrid, genetic epistasis, vacuolar acidification assay, protein stability assay","journal":"Eukaryotic cell","confidence":"Medium","confidence_rationale":"Tier 2–3 — protein interactions combined with functional assays, single lab","pmids":["21097665"],"is_preprint":false},{"year":2011,"finding":"Human SEC63 interacts with nucleoredoxin (NRX), a cytosolic protein involved in Wnt signaling, as identified by yeast two-hybrid screen, providing a potential mechanistic link between SEC63 mutations and polycystic liver disease via Wnt pathway dysregulation.","method":"Yeast two-hybrid screen, interaction characterization","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 3 — single Y2H finding, no functional follow-up in mammalian cells","pmids":["21251912"],"is_preprint":false},{"year":2012,"finding":"Knockdown of SEC63 in human HeLa cells inhibits co-translational protein transport of specific signal-peptide-containing precursors into the ER in a precursor-specific manner, whereas SEC62 knockdown inhibits only post-translational transport, demonstrating distinct substrate specificities for each component.","method":"siRNA knockdown, semi-permeabilized cell translocation assay, pulse-chase","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined substrate-specific phenotypic readout, multiple substrates tested","pmids":["22375059"],"is_preprint":false},{"year":2012,"finding":"Overexpression of human SEC63 reduces steady-state levels of multi-spanning membrane proteins in a co-translational mode; a J-domain mutation that weakens BiP interaction reduces this effect, indicating that SEC63's regulatory function on polytopic ER client proteins requires its interaction with BiP.","method":"Overexpression and knockdown in human cells, Western blot quantification, J-domain mutagenesis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 — mutagenesis combined with functional readout, single lab","pmids":["23166619"],"is_preprint":false},{"year":2012,"finding":"Protein kinase CK2 phosphorylates human SEC63 at serine 574, serine 576, and serine 748; this phosphorylation enhances SEC63 binding to SEC62, regulating assembly of a functional ER protein translocon.","method":"In vitro kinase assay with deletion mutants and peptide library, pull-down assay, co-immunoprecipitation","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — phosphorylation sites mapped biochemically with functional consequence on complex assembly, single lab","pmids":["23287549"],"is_preprint":false},{"year":2014,"finding":"Mutations in the N-terminal cytosolic domain of yeast SEC62 that impair its interaction with SEC63 cause defects in membrane insertion and C-terminal translocation of single- and multi-spanning membrane proteins, revealing a role for the SEC62-SEC63 translocon in topogenesis of membrane proteins beyond secretory proteins.","method":"Mutagenesis, in vivo translocation assays, interaction analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis with defined functional translocation phenotype, single lab","pmids":["25097231"],"is_preprint":false},{"year":2015,"finding":"SEC63 deficiency in mice selectively activates the IRE1α-XBP1 branch of the unfolded protein response (UPR); SEC63 exists in a complex with polycystin-1 (PC1); concomitant loss of SEC63 and XBP1 suppresses GPS cleavage of PC1 and worsens polycystic kidney disease; enforced XBP1s expression rescues GPS cleavage and ameliorates cyst formation.","method":"Murine genetic models (conditional knockout), co-immunoprecipitation, PC1 GPS cleavage assay, in vivo rescue by XBP1s overexpression","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, genetic epistasis, in vivo rescue) in a single rigorous study","pmids":["25844898"],"is_preprint":false},{"year":2019,"finding":"The N-terminal 39 residues of yeast SEC63 are required for stability of the SEC complex (SEC61 + SEC62/SEC63); deletion of this region impairs post-translational translocation and proper sorting of single- and double-pass membrane proteins.","method":"SEC63 N-terminal deletion mutant, Blue-Native PAGE, metabolic labeling translocation assay","journal":"Biochimica et biophysica acta. General subjects","confidence":"Medium","confidence_rationale":"Tier 2 — domain deletion combined with complex stability assay and functional translocation readout, single lab","pmids":["31195072"],"is_preprint":false},{"year":2019,"finding":"Inactivation of SEC63 together with IRE1α or XBP1 specifically in collecting duct cells causes interstitial inflammation, fibrosis, and kidney functional decline; re-expression of XBP1s fully rescues this injury, demonstrating that basal IRE1α-XBP1 activity is required for proteostasis in SEC63-deficient collecting duct cells.","method":"Conditional knockout mouse models (collecting duct-specific), histology, kidney function assays, in vivo XBP1s re-expression","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 2 — multiple conditional KO combinations with clear phenotypic rescue, rigorous in vivo epistasis","pmids":["30745418"],"is_preprint":false},{"year":2020,"finding":"Human SEC62/SEC63 complex substrates share signal peptides with longer but less hydrophobic H-regions and lower C-region polarity; mechanistically, a slowly gating signal peptide combined with a downstream positively charged cluster requires SEC62/SEC63 and BiP for efficient SEC61 channel opening and translocation.","method":"Proteomics (unbiased substrate identification in intact cells), in vitro translocation assay, SEC63/SEC62 knockdown, signal peptide mutagenesis","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 — unbiased proteomics combined with functional knockdown and mutagenesis experiments defining substrate rules","pmids":["32133789"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structures of yeast SEC61-SEC62-SEC63 complexes show that SEC63 induces partial opening of the SEC61 lateral gate through cytosolic and luminal domain contacts, while SEC62 is additionally required to displace the SEC61 plug domain and open the translocation pore; molecular dynamics simulations further suggest SEC62 prevents lipid invasion through the open lateral gate.","method":"Cryo-EM structure determination, molecular dynamics simulations, mutagenesis of SEC61-SEC63 contact sites","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 — high-resolution cryo-EM structures with functional validation by mutagenesis and MD simulations","pmids":["33398175"],"is_preprint":false},{"year":2021,"finding":"Molecular dynamics simulations and co-precipitation experiments show that SEC61 subunit Sbh1 is not required for stable SEC63-SEC61 contacts; SEC63 modulates the conformation of the SEC61 lateral gate, plug, pore region, and pore ring via three intermolecular contact regions, and these changes differentially position SRP-dependent versus SRP-independent signal peptides within the channel.","method":"Co-precipitation, molecular dynamics simulation, molecular docking of signal peptides","journal":"PLoS computational biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — co-precipitation plus computational modeling; primarily computational but grounded in structural data","pmids":["33780447"],"is_preprint":false},{"year":2021,"finding":"SOX9 transcriptionally regulates SEC63 expression in biliary epithelial cells; liver-specific Sox9 knockout mice show reduced Sec63, and SEC63 overexpression partially rescues primary cilia formation and proliferation defects caused by SOX9 depletion.","method":"Chromatin immunoprecipitation, luciferase reporter assay, siRNA knockdown, SEC63 overexpression rescue","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assay establish direct transcriptional regulation, functional rescue with overexpression","pmids":["33512716"],"is_preprint":false},{"year":2023,"finding":"Upon ER stress, IRE1α phosphorylates SEC63 at T537; phosphorylated SEC63 stabilizes ACLY protein (increasing acetyl-CoA and lipid biosynthesis) and translocates to the nucleus to increase nuclear acetyl-CoA production; SEC63 and ACLY cooperate to epigenetically upregulate Snail1, promoting HCC metastasis.","method":"GST pull-down, co-immunoprecipitation/mass spectrometry, in vivo ubiquitination/phosphorylation assay, immunofluorescence, RNA-sequencing, metabolite detection, transwell assay","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical methods (pulldown, IP-MS, phosphorylation assay) in a single study, single lab","pmids":["37122003"],"is_preprint":false},{"year":2024,"finding":"LncRNA WFDC21P physically binds SEC63 protein (validated by RNA pulldown and RNA immunoprecipitation) and regulates SEC63 expression; this interaction modulates the calcium homeostasis signaling pathway to promote gastric cancer proliferation, migration, and invasion.","method":"RNA pulldown, RNA immunoprecipitation, siRNA knockdown, Western blot, functional cell assays","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 — single lab, pulldown and RIP without detailed mechanistic dissection of how WFDC21P regulates SEC63","pmids":["38528582"],"is_preprint":false},{"year":2026,"finding":"Palmitoylation of SEC63 at cysteine 490 (and potentially other sites) regulated by palmitic acid promotes ER stress in ovarian granulosa cells; mutation of SEC63 palmitoylation sites reduces GRP78, CHOP, and ATF6 expression, indicating that palmitoylation modification of SEC63 contributes to ER stress induction.","method":"Palmitoylation-modified proteomics, site-directed mutagenesis of palmitoylation sites, Western blot for ER stress markers","journal":"Journal of ovarian research","confidence":"Low","confidence_rationale":"Tier 3 — single lab, mutagenesis with protein-level readout but no biochemical confirmation of palmitoylation site by acyl-RAC or ABE assay","pmids":["41845436"],"is_preprint":false}],"current_model":"SEC63 is an ER transmembrane J-domain co-chaperone that associates with the SEC61 protein-conducting channel (together with SEC62) to form the post-translational translocon; structurally, SEC63 induces partial opening of the SEC61 lateral gate while SEC62 displaces the plug domain to fully activate the channel for translocation of substrates bearing slowly gating or suboptimal signal peptides; SEC63 cooperates with BiP/KAR2 via its J-domain for client delivery, is phosphorylated by CK2 to enhance SEC62 binding, and in addition to its canonical translocation role, SEC63 regulates the IRE1α-XBP1 branch of the UPR, exists in a complex with polycystin-1, and is required for GPS cleavage and maturation of polycystin-1, thereby suppressing polycystic disease."},"narrative":{"teleology":[{"year":1993,"claim":"Establishing that SEC63 functionally cooperates with the ER luminal Hsp70 chaperone Kar2/BiP resolved how the J-domain of an ER translocon component couples to a chaperone motor for substrate translocation.","evidence":"Allele-specific suppression, synthetic lethality, and Northern blot in yeast sec63/kar2 mutants","pmids":["8305736"],"confidence":"High","gaps":["Direct physical contact between SEC63 J-domain and Kar2 was inferred genetically, not shown biochemically in this study","Whether SEC63–Kar2 cooperation extends to co-translational substrates was not tested"]},{"year":1993,"claim":"Identification of SEC66/HSS1 and SON1–SON5 as suppressors of sec63 alleles expanded the translocon to additional subunits and hinted at SEC63 roles beyond secretory protein import.","evidence":"High-copy and extragenic suppressor screens in yeast, translocation precursor accumulation assays","pmids":["8257794","8514125"],"confidence":"Medium","gaps":["Mechanistic basis of SON1-mediated suppression of sec63 was not determined","Whether SEC66 is a stable stoichiometric subunit or regulatory factor was unclear"]},{"year":2000,"claim":"Demonstrating that mammalian SEC63 forms a ribosome-free complex with SEC61 and SEC62 established the existence of a dedicated post-translational translocon in the mammalian ER, resolving whether yeast findings were conserved.","evidence":"Biochemical fractionation and co-immunoprecipitation from mammalian ER membranes","pmids":["10799540"],"confidence":"High","gaps":["Substrate identity for the mammalian SEC62/SEC63 translocon was unknown","Structural organization of the complex was not resolved"]},{"year":2004,"claim":"Identifying SEC63 loss-of-function mutations as the genetic cause of autosomal dominant polycystic liver disease linked ER translocation machinery to organ-level cystic pathology for the first time.","evidence":"Genetic mapping and mutation sequencing in affected human families","pmids":["15133510"],"confidence":"High","gaps":["Which SEC63-dependent client protein(s) are responsible for cystogenesis was unknown","Whether haploinsufficiency or a two-hit mechanism drives disease was not established"]},{"year":2012,"claim":"siRNA studies distinguished SEC63 from SEC62 substrate specificity: SEC63 is required for co-translational transport of specific signal-peptide precursors, not solely post-translational substrates, broadening its functional scope.","evidence":"siRNA knockdown in HeLa cells with semi-permeabilized cell translocation assays for multiple defined substrates","pmids":["22375059"],"confidence":"High","gaps":["Signal peptide features that determine SEC63 dependence were not yet defined","Whether BiP/J-domain interaction is required for the co-translational role was not tested"]},{"year":2012,"claim":"Mapping CK2-mediated phosphorylation of SEC63 at S574, S576, and S748 and showing it enhances SEC62 binding revealed a post-translational regulatory mechanism for translocon assembly.","evidence":"In vitro kinase assays, pull-down and co-immunoprecipitation in human cells","pmids":["23287549"],"confidence":"Medium","gaps":["In vivo phosphorylation dynamics and whether CK2 activity is regulated under ER stress were not examined","Functional consequence of phosphorylation on translocation efficiency was not directly measured"]},{"year":2015,"claim":"Showing that SEC63 deficiency selectively activates the IRE1α–XBP1 UPR branch and that SEC63 complexes with polycystin-1 to regulate its GPS cleavage provided a mechanistic link from the translocon to cystic disease pathogenesis.","evidence":"Conditional knockout mice, co-immunoprecipitation, PC1 GPS cleavage assay, in vivo XBP1s rescue","pmids":["25844898"],"confidence":"High","gaps":["How SEC63 physically promotes GPS cleavage of PC1 was not resolved","Whether the SEC63–PC1 interaction is direct or mediated by the translocon complex was not determined"]},{"year":2019,"claim":"Demonstrating that combined loss of SEC63 and IRE1α/XBP1 in collecting duct causes kidney injury rescuable by XBP1s established that basal UPR compensates for SEC63 loss to maintain renal proteostasis.","evidence":"Collecting duct–specific conditional knockout mice with functional and histological phenotyping, XBP1s re-expression rescue","pmids":["30745418"],"confidence":"High","gaps":["Identity of the critical XBP1 target genes that compensate for SEC63 loss was not defined"]},{"year":2020,"claim":"Unbiased proteomic identification of SEC62/SEC63-dependent substrates and signal peptide mutagenesis defined the biochemical rules — long but less hydrophobic H-regions and downstream positive charges — that create SEC63 dependence, explaining substrate selectivity.","evidence":"Proteomics in intact human cells, in vitro translocation, signal peptide mutagenesis","pmids":["32133789"],"confidence":"High","gaps":["Whether these rules apply universally across cell types and species was not tested","Structural basis for how suboptimal signal peptides engage SEC63-activated SEC61 was unknown"]},{"year":2021,"claim":"Cryo-EM structures of the SEC61–SEC62–SEC63 complex revealed that SEC63 partially opens the SEC61 lateral gate while SEC62 displaces the plug, providing an atomic-level mechanism for how the auxiliary translocon activates the channel.","evidence":"Cryo-EM at near-atomic resolution, molecular dynamics simulations, mutagenesis of contact residues in yeast","pmids":["33398175"],"confidence":"High","gaps":["Structures of the complex engaged with a translocating substrate are lacking","How BiP/J-domain action is coordinated with gate opening at the structural level remains unresolved"]},{"year":2023,"claim":"Discovery that IRE1α phosphorylates SEC63 at T537 under ER stress, promoting ACLY stabilization and nuclear translocation to drive lipid biosynthesis and epigenetic activation of Snail1, suggested a non-canonical role for SEC63 in cancer metastasis.","evidence":"GST pull-down, IP-MS, phosphorylation/ubiquitination assays, RNA-seq, metabolite detection in HCC cell lines","pmids":["37122003"],"confidence":"Medium","gaps":["Nuclear translocation of an ER transmembrane protein lacks mechanistic explanation for membrane release","Whether the SEC63–ACLY axis operates outside hepatocellular carcinoma contexts is unknown","Independent replication is needed"]},{"year":null,"claim":"Key unresolved questions include the structural basis of SEC63 J-domain–BiP coupling during active translocation, the direct versus indirect nature of the SEC63–polycystin-1 interaction, and whether SEC63 phosphorylation and palmitoylation integrate to tune translocon activity under physiological stress.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of the active SEC63–BiP–substrate ternary complex exists","Palmitoylation of SEC63 at C490 has not been validated by orthogonal acyl-capture assays","Two-hit versus haploinsufficiency mechanism in PCLD remains genetically unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[1,9,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,15,16]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,5,8,16]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,8,15,16]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,8,9,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,12,14]}],"complexes":["SEC61-SEC62-SEC63 translocon","SEC62/SEC63 post-translational translocon"],"partners":["SEC61A1","SEC62","SEC66","SEC72","HSPA5","PKD1","CSNK2A1","ACLY"],"other_free_text":[]},"mechanistic_narrative":"SEC63 is an ER-resident transmembrane J-domain co-chaperone that partners with SEC61 and SEC62 to form the post-translational protein translocation channel, and additionally facilitates co-translational import of precursors bearing slowly gating or suboptimal signal peptides [PMID:10799540, PMID:22375059, PMID:32133789]. Cryo-EM structures show that SEC63 induces partial opening of the SEC61 lateral gate through cytosolic and luminal domain contacts, while its J-domain recruits BiP/Kar2 to drive substrate translocation; CK2-mediated phosphorylation of SEC63 enhances SEC62 binding to complete channel activation [PMID:33398175, PMID:8305736, PMID:23287549]. Beyond translocation, SEC63 deficiency selectively activates the IRE1α–XBP1 branch of the UPR and impairs GPS cleavage and maturation of polycystin-1, linking SEC63 to polycystic kidney and liver disease [PMID:25844898, PMID:30745418]. Loss-of-function mutations in SEC63 cause autosomal dominant polycystic liver disease in humans [PMID:15133510]."},"prefetch_data":{"uniprot":{"accession":"Q9UGP8","full_name":"Translocation protein SEC63 homolog","aliases":["DnaJ homolog subfamily C member 23"],"length_aa":760,"mass_kda":88.0,"function":"Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER) (PubMed:22375059, PubMed:29719251). Proposed to play an auxiliary role in recognition of precursors with short and apolar signal peptides. May cooperate with SEC62 and HSPA5/BiP to facilitate targeting of small presecretory proteins into the SEC61 channel-forming translocon complex, triggering channel opening for polypeptide translocation to the ER lumen (PubMed:29719251). Required for efficient PKD1/Polycystin-1 biogenesis and trafficking to the plasma membrane of the primary cilia (By similarity)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9UGP8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SEC63","classification":"Common Essential","n_dependent_lines":756,"n_total_lines":1208,"dependency_fraction":0.6258278145695364},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SEC61B","stoichiometry":10.0},{"gene":"VAPA","stoichiometry":0.2},{"gene":"VAPB","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2},{"gene":"NCLN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SEC63","total_profiled":1310},"omim":[{"mim_id":"618271","title":"SEC61 TRANSLOCON, ALPHA-2 SUBUNIT; SEC61A2","url":"https://www.omim.org/entry/618271"},{"mim_id":"617874","title":"POLYCYSTIC LIVER DISEASE 3 WITH OR WITHOUT KIDNEY CYSTS; PCLD3","url":"https://www.omim.org/entry/617874"},{"mim_id":"617004","title":"POLYCYSTIC LIVER DISEASE 2 WITH OR WITHOUT KIDNEY CYSTS; PCLD2","url":"https://www.omim.org/entry/617004"},{"mim_id":"615684","title":"HELICASE FOR MEIOSIS 1; HFM1","url":"https://www.omim.org/entry/615684"},{"mim_id":"614217","title":"ACTIVATING SIGNAL COINTEGRATOR 1 COMPLEX, SUBUNIT 3; ASCC3","url":"https://www.omim.org/entry/614217"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEC63"},"hgnc":{"alias_symbol":["SEC63L","PRO2507","ERdj2","DNAJC23"],"prev_symbol":[]},"alphafold":{"accession":"Q9UGP8","domains":[{"cath_id":"-","chopping":"6-94","consensus_level":"high","plddt":87.536,"start":6,"end":94},{"cath_id":"1.10.287.110","chopping":"104-153","consensus_level":"high","plddt":88.302,"start":104,"end":153},{"cath_id":"1.10.3380.10","chopping":"219-371","consensus_level":"high","plddt":90.8883,"start":219,"end":371},{"cath_id":"2.60.40.150","chopping":"450-485_629-715","consensus_level":"medium","plddt":89.7985,"start":450,"end":715},{"cath_id":"1.20.5","chopping":"185-215","consensus_level":"high","plddt":92.7758,"start":185,"end":215}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UGP8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UGP8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UGP8-F1-predicted_aligned_error_v6.png","plddt_mean":77.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEC63","jax_strain_url":"https://www.jax.org/strain/search?query=SEC63"},"sequence":{"accession":"Q9UGP8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UGP8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UGP8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UGP8"}},"corpus_meta":[{"pmid":"15133510","id":"PMC_15133510","title":"Mutations in SEC63 cause autosomal dominant polycystic liver disease.","date":"2004","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15133510","citation_count":195,"is_preprint":false},{"pmid":"10799540","id":"PMC_10799540","title":"Mammalian Sec61 is associated with Sec62 and Sec63.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10799540","citation_count":158,"is_preprint":false},{"pmid":"29263911","id":"PMC_29263911","title":"Let's talk about Secs: Sec61, Sec62 and Sec63 in signal transduction, oncology and personalized medicine.","date":"2017","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29263911","citation_count":137,"is_preprint":false},{"pmid":"22375059","id":"PMC_22375059","title":"Different effects of Sec61α, Sec62 and Sec63 depletion on transport of polypeptides into the endoplasmic reticulum of mammalian cells.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/22375059","citation_count":133,"is_preprint":false},{"pmid":"8305736","id":"PMC_8305736","title":"Genetic interactions between KAR2 and SEC63, encoding eukaryotic homologues of DnaK and DnaJ in the endoplasmic reticulum.","date":"1993","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/8305736","citation_count":125,"is_preprint":false},{"pmid":"8514125","id":"PMC_8514125","title":"Extragenic suppressors of mutations in the cytoplasmic C terminus of SEC63 define five genes in Saccharomyces cerevisiae.","date":"1993","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8514125","citation_count":54,"is_preprint":false},{"pmid":"37122003","id":"PMC_37122003","title":"Activation of ACLY by SEC63 deploys metabolic reprogramming to facilitate hepatocellular carcinoma metastasis upon endoplasmic reticulum stress.","date":"2023","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/37122003","citation_count":51,"is_preprint":false},{"pmid":"25844898","id":"PMC_25844898","title":"Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity.","date":"2015","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/25844898","citation_count":51,"is_preprint":false},{"pmid":"33398175","id":"PMC_33398175","title":"Stepwise gating of the Sec61 protein-conducting channel by Sec63 and Sec62.","date":"2021","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/33398175","citation_count":49,"is_preprint":false},{"pmid":"32133789","id":"PMC_32133789","title":"Identification of signal peptide features for substrate specificity in human Sec62/Sec63-dependent ER protein import.","date":"2020","source":"The FEBS 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genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20095989","citation_count":32,"is_preprint":false},{"pmid":"12518317","id":"PMC_12518317","title":"Identification of novel protein-protein interactions at the cytosolic surface of the Sec63 complex in the yeast ER membrane.","date":"2003","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/12518317","citation_count":30,"is_preprint":false},{"pmid":"25097231","id":"PMC_25097231","title":"The Sec62-Sec63 translocon facilitates translocation of the C-terminus of membrane proteins.","date":"2014","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/25097231","citation_count":29,"is_preprint":false},{"pmid":"34884562","id":"PMC_34884562","title":"Emerging View on the Molecular Functions of Sec62 and Sec63 in Protein Translocation.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34884562","citation_count":26,"is_preprint":false},{"pmid":"23209713","id":"PMC_23209713","title":"Loss of heterozygosity is present in SEC63 germline carriers with polycystic liver disease.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23209713","citation_count":25,"is_preprint":false},{"pmid":"23537056","id":"PMC_23537056","title":"Hepatocellular carcinoma as extracolonic manifestation of Lynch syndrome indicates SEC63 as potential target gene in hepatocarcinogenesis.","date":"2013","source":"Scandinavian journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/23537056","citation_count":22,"is_preprint":false},{"pmid":"22864019","id":"PMC_22864019","title":"Mutation of sec63 in zebrafish causes defects in myelinated axons and liver pathology.","date":"2012","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/22864019","citation_count":21,"is_preprint":false},{"pmid":"23287549","id":"PMC_23287549","title":"CK2 phosphorylation of human Sec63 regulates its interaction with Sec62.","date":"2012","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23287549","citation_count":20,"is_preprint":false},{"pmid":"30745418","id":"PMC_30745418","title":"Spliced XBP1 Rescues Renal Interstitial Inflammation Due to Loss of Sec63 in Collecting Ducts.","date":"2019","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/30745418","citation_count":19,"is_preprint":false},{"pmid":"21251912","id":"PMC_21251912","title":"An interaction between human Sec63 and nucleoredoxin may provide the missing link between the SEC63 gene and polycystic liver disease.","date":"2011","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/21251912","citation_count":19,"is_preprint":false},{"pmid":"23166619","id":"PMC_23166619","title":"Role of human sec63 in modulating the steady-state levels of multi-spanning membrane proteins.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23166619","citation_count":15,"is_preprint":false},{"pmid":"21097665","id":"PMC_21097665","title":"Hph1 and Hph2 are novel components of the Sec63/Sec62 posttranslational translocation complex that aid in vacuolar proton ATPase biogenesis.","date":"2010","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/21097665","citation_count":15,"is_preprint":false},{"pmid":"33780447","id":"PMC_33780447","title":"How does Sec63 affect the conformation of Sec61 in yeast?","date":"2021","source":"PLoS computational biology","url":"https://pubmed.ncbi.nlm.nih.gov/33780447","citation_count":12,"is_preprint":false},{"pmid":"25428373","id":"PMC_25428373","title":"Brr2p carboxy-terminal Sec63 domain modulates Prp16 splicing RNA helicase.","date":"2014","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/25428373","citation_count":12,"is_preprint":false},{"pmid":"33977099","id":"PMC_33977099","title":"SEC62 and SEC63 Expression in Hepatocellular Carcinoma and Tumor-Surrounding Liver Tissue.","date":"2021","source":"Visceral medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33977099","citation_count":11,"is_preprint":false},{"pmid":"31195072","id":"PMC_31195072","title":"Proper insertion and topogenesis of membrane proteins in the ER depend on Sec63.","date":"2019","source":"Biochimica et biophysica acta. General subjects","url":"https://pubmed.ncbi.nlm.nih.gov/31195072","citation_count":10,"is_preprint":false},{"pmid":"33512716","id":"PMC_33512716","title":"Deletion of Sox9 in the liver leads to hepatic cystogenesis in mice by transcriptionally downregulating Sec63.","date":"2021","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/33512716","citation_count":10,"is_preprint":false},{"pmid":"31754327","id":"PMC_31754327","title":"microRNA-1 Regulates NCC Migration and Differentiation by Targeting sec63.","date":"2019","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31754327","citation_count":9,"is_preprint":false},{"pmid":"19208265","id":"PMC_19208265","title":"The uterine expression of SEC63 gene is up-regulated at implantation sites in association with the decidualization during the early pregnancy in mice.","date":"2009","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/19208265","citation_count":3,"is_preprint":false},{"pmid":"38528582","id":"PMC_38528582","title":"LncRNA WFDC21P interacts with SEC63 to promote gastric cancer malignant behaviors by regulating calcium homeostasis signaling pathway.","date":"2024","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/38528582","citation_count":2,"is_preprint":false},{"pmid":"30558886","id":"PMC_30558886","title":"FBP21's C-Terminal Domain Remains Dynamic When Wrapped around the c-Sec63 Unit of Brr2 Helicase.","date":"2018","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/30558886","citation_count":2,"is_preprint":false},{"pmid":"9153759","id":"PMC_9153759","title":"Sequencing analysis of a 36.8 kb fragment of yeast chromosome XV reveals 26 open reading frames including SEC63, CDC31, SUG2, GCD1, RBL2, PNT1, PAC1 and VPH1.","date":"1997","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9153759","citation_count":1,"is_preprint":false},{"pmid":"41994676","id":"PMC_41994676","title":"Clinical and Genetic Characterization of a Patient With SEC63-Related Autosomal Dominant Polycystic Liver Disease and an IFT140 Pathogenic Variant Associated With Polycystic Kidney Disease.","date":"2026","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/41994676","citation_count":0,"is_preprint":false},{"pmid":"40558980","id":"PMC_40558980","title":"Sec61s and Sec62/Sec63 Genes Are Essential for Survival by Regulating the Gut and Cuticle Development in Locusta migratoria.","date":"2025","source":"Insects","url":"https://pubmed.ncbi.nlm.nih.gov/40558980","citation_count":0,"is_preprint":false},{"pmid":"41845436","id":"PMC_41845436","title":"Role and mechanism of palmitic acid-regulated palmitoylation modification of SEC63 protein during endoplasmic reticulum stress in human ovarian granulosa tumor cells (KGN).","date":"2026","source":"Journal of ovarian research","url":"https://pubmed.ncbi.nlm.nih.gov/41845436","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.30.667231","title":"Protein secretion routes in fungi are mostly determined by the length of the hydrophobic helix in the signal peptide","date":"2025-07-31","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.30.667231","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.11.659973","title":"Context-dependent regulatory variants in Alzheimer’s disease","date":"2025-07-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.11.659973","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19892,"output_tokens":4736,"usd":0.065358},"stage2":{"model":"claude-opus-4-6","input_tokens":8287,"output_tokens":2852,"usd":0.169102},"total_usd":0.23446,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Mammalian SEC63 forms a ribosome-free complex with SEC61 and SEC62 in the ER membrane, representing a post-translational translocation apparatus distinct from the ribosome-bound SEC61 complex used for co-translational import.\",\n      \"method\": \"Biochemical fractionation, primary sequence homology analysis, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-purification establishing complex membership, replicated across subsequent studies\",\n      \"pmids\": [\"10799540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Yeast SEC63p (DnaJ homolog) genetically interacts with KAR2/BiP (DnaK homolog) in the ER: temperature-sensitive kar2 and sec63 mutations form synthetic lethals, dominant KAR2 mutations suppress sec63-1 in an allele-specific manner, and sec63-1 induces KAR2 transcription, indicating direct functional cooperation in protein translocation.\",\n      \"method\": \"Genetic epistasis, suppressor analysis, allele-specific suppression, mRNA Northern blot\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genetic approaches showing allele-specific interaction, foundational study\",\n      \"pmids\": [\"8305736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Suppressor screen of sec63-101 in yeast identified SON1-SON5 genes; SON1 encodes a nuclear protein whose loss suppresses sec63 alleles with regional specificity, placing SEC63 in a pathway important for both ER translocation and nuclear protein localization.\",\n      \"method\": \"Extragenic suppressor screen, genetic complementation, gene cloning and sequencing\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis by suppressor genetics, single lab\",\n      \"pmids\": [\"8514125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"High-copy suppressor screen of sec63-101 identified HSS1/SEC66, an integral ER membrane glycoprotein that physically associates with SEC62p and SEC63p; disruption of HSS1 causes accumulation of translocation precursors, placing HSS1/SEC66 as a functional component of the yeast translocation apparatus.\",\n      \"method\": \"High-copy suppressor screen, genetic disruption, precursor accumulation assay, complex co-purification\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — suppressor genetics combined with functional translocation assay and complex identification\",\n      \"pmids\": [\"8257794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In yeast, SEC62p and SEC63p interact directly at their cytosolic surfaces; SEC72p homodimerizes; and YLR301w (novel protein) was identified as an in vivo interacting partner of SEC72p within the SEC62/SEC63 tetrameric complex.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, domain mapping\",\n      \"journal\": \"Yeast (Chichester, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct interaction between essential subunits confirmed by Y2H and Co-IP, single lab\",\n      \"pmids\": [\"12518317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Loss-of-function mutations in SEC63, encoding an ER protein translocation component, cause autosomal dominant polycystic liver disease in humans, implicating co-translational ER protein-processing pathways in maintaining biliary epithelial luminal structure.\",\n      \"method\": \"Human genetic mapping, mutation identification by sequencing, disease association\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — disease-causing mutations defined in multiple families, foundational paper with 195 citations\",\n      \"pmids\": [\"15133510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Hph1 and Hph2, integral ER membrane proteins, interact with SEC63, SEC62, SEC71, and SEC72 of the yeast SEC63/SEC62 post-translational translocation complex, and loss of Hph1/Hph2 along with the complex impairs biogenesis of vacuolar proton ATPase subunit Vph1.\",\n      \"method\": \"Split-ubiquitin two-hybrid, genetic epistasis, vacuolar acidification assay, protein stability assay\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — protein interactions combined with functional assays, single lab\",\n      \"pmids\": [\"21097665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human SEC63 interacts with nucleoredoxin (NRX), a cytosolic protein involved in Wnt signaling, as identified by yeast two-hybrid screen, providing a potential mechanistic link between SEC63 mutations and polycystic liver disease via Wnt pathway dysregulation.\",\n      \"method\": \"Yeast two-hybrid screen, interaction characterization\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Y2H finding, no functional follow-up in mammalian cells\",\n      \"pmids\": [\"21251912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Knockdown of SEC63 in human HeLa cells inhibits co-translational protein transport of specific signal-peptide-containing precursors into the ER in a precursor-specific manner, whereas SEC62 knockdown inhibits only post-translational transport, demonstrating distinct substrate specificities for each component.\",\n      \"method\": \"siRNA knockdown, semi-permeabilized cell translocation assay, pulse-chase\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined substrate-specific phenotypic readout, multiple substrates tested\",\n      \"pmids\": [\"22375059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Overexpression of human SEC63 reduces steady-state levels of multi-spanning membrane proteins in a co-translational mode; a J-domain mutation that weakens BiP interaction reduces this effect, indicating that SEC63's regulatory function on polytopic ER client proteins requires its interaction with BiP.\",\n      \"method\": \"Overexpression and knockdown in human cells, Western blot quantification, J-domain mutagenesis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — mutagenesis combined with functional readout, single lab\",\n      \"pmids\": [\"23166619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Protein kinase CK2 phosphorylates human SEC63 at serine 574, serine 576, and serine 748; this phosphorylation enhances SEC63 binding to SEC62, regulating assembly of a functional ER protein translocon.\",\n      \"method\": \"In vitro kinase assay with deletion mutants and peptide library, pull-down assay, co-immunoprecipitation\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — phosphorylation sites mapped biochemically with functional consequence on complex assembly, single lab\",\n      \"pmids\": [\"23287549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mutations in the N-terminal cytosolic domain of yeast SEC62 that impair its interaction with SEC63 cause defects in membrane insertion and C-terminal translocation of single- and multi-spanning membrane proteins, revealing a role for the SEC62-SEC63 translocon in topogenesis of membrane proteins beyond secretory proteins.\",\n      \"method\": \"Mutagenesis, in vivo translocation assays, interaction analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis with defined functional translocation phenotype, single lab\",\n      \"pmids\": [\"25097231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SEC63 deficiency in mice selectively activates the IRE1α-XBP1 branch of the unfolded protein response (UPR); SEC63 exists in a complex with polycystin-1 (PC1); concomitant loss of SEC63 and XBP1 suppresses GPS cleavage of PC1 and worsens polycystic kidney disease; enforced XBP1s expression rescues GPS cleavage and ameliorates cyst formation.\",\n      \"method\": \"Murine genetic models (conditional knockout), co-immunoprecipitation, PC1 GPS cleavage assay, in vivo rescue by XBP1s overexpression\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, genetic epistasis, in vivo rescue) in a single rigorous study\",\n      \"pmids\": [\"25844898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The N-terminal 39 residues of yeast SEC63 are required for stability of the SEC complex (SEC61 + SEC62/SEC63); deletion of this region impairs post-translational translocation and proper sorting of single- and double-pass membrane proteins.\",\n      \"method\": \"SEC63 N-terminal deletion mutant, Blue-Native PAGE, metabolic labeling translocation assay\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain deletion combined with complex stability assay and functional translocation readout, single lab\",\n      \"pmids\": [\"31195072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Inactivation of SEC63 together with IRE1α or XBP1 specifically in collecting duct cells causes interstitial inflammation, fibrosis, and kidney functional decline; re-expression of XBP1s fully rescues this injury, demonstrating that basal IRE1α-XBP1 activity is required for proteostasis in SEC63-deficient collecting duct cells.\",\n      \"method\": \"Conditional knockout mouse models (collecting duct-specific), histology, kidney function assays, in vivo XBP1s re-expression\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple conditional KO combinations with clear phenotypic rescue, rigorous in vivo epistasis\",\n      \"pmids\": [\"30745418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human SEC62/SEC63 complex substrates share signal peptides with longer but less hydrophobic H-regions and lower C-region polarity; mechanistically, a slowly gating signal peptide combined with a downstream positively charged cluster requires SEC62/SEC63 and BiP for efficient SEC61 channel opening and translocation.\",\n      \"method\": \"Proteomics (unbiased substrate identification in intact cells), in vitro translocation assay, SEC63/SEC62 knockdown, signal peptide mutagenesis\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — unbiased proteomics combined with functional knockdown and mutagenesis experiments defining substrate rules\",\n      \"pmids\": [\"32133789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structures of yeast SEC61-SEC62-SEC63 complexes show that SEC63 induces partial opening of the SEC61 lateral gate through cytosolic and luminal domain contacts, while SEC62 is additionally required to displace the SEC61 plug domain and open the translocation pore; molecular dynamics simulations further suggest SEC62 prevents lipid invasion through the open lateral gate.\",\n      \"method\": \"Cryo-EM structure determination, molecular dynamics simulations, mutagenesis of SEC61-SEC63 contact sites\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM structures with functional validation by mutagenesis and MD simulations\",\n      \"pmids\": [\"33398175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Molecular dynamics simulations and co-precipitation experiments show that SEC61 subunit Sbh1 is not required for stable SEC63-SEC61 contacts; SEC63 modulates the conformation of the SEC61 lateral gate, plug, pore region, and pore ring via three intermolecular contact regions, and these changes differentially position SRP-dependent versus SRP-independent signal peptides within the channel.\",\n      \"method\": \"Co-precipitation, molecular dynamics simulation, molecular docking of signal peptides\",\n      \"journal\": \"PLoS computational biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-precipitation plus computational modeling; primarily computational but grounded in structural data\",\n      \"pmids\": [\"33780447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SOX9 transcriptionally regulates SEC63 expression in biliary epithelial cells; liver-specific Sox9 knockout mice show reduced Sec63, and SEC63 overexpression partially rescues primary cilia formation and proliferation defects caused by SOX9 depletion.\",\n      \"method\": \"Chromatin immunoprecipitation, luciferase reporter assay, siRNA knockdown, SEC63 overexpression rescue\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assay establish direct transcriptional regulation, functional rescue with overexpression\",\n      \"pmids\": [\"33512716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Upon ER stress, IRE1α phosphorylates SEC63 at T537; phosphorylated SEC63 stabilizes ACLY protein (increasing acetyl-CoA and lipid biosynthesis) and translocates to the nucleus to increase nuclear acetyl-CoA production; SEC63 and ACLY cooperate to epigenetically upregulate Snail1, promoting HCC metastasis.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation/mass spectrometry, in vivo ubiquitination/phosphorylation assay, immunofluorescence, RNA-sequencing, metabolite detection, transwell assay\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods (pulldown, IP-MS, phosphorylation assay) in a single study, single lab\",\n      \"pmids\": [\"37122003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LncRNA WFDC21P physically binds SEC63 protein (validated by RNA pulldown and RNA immunoprecipitation) and regulates SEC63 expression; this interaction modulates the calcium homeostasis signaling pathway to promote gastric cancer proliferation, migration, and invasion.\",\n      \"method\": \"RNA pulldown, RNA immunoprecipitation, siRNA knockdown, Western blot, functional cell assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, pulldown and RIP without detailed mechanistic dissection of how WFDC21P regulates SEC63\",\n      \"pmids\": [\"38528582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Palmitoylation of SEC63 at cysteine 490 (and potentially other sites) regulated by palmitic acid promotes ER stress in ovarian granulosa cells; mutation of SEC63 palmitoylation sites reduces GRP78, CHOP, and ATF6 expression, indicating that palmitoylation modification of SEC63 contributes to ER stress induction.\",\n      \"method\": \"Palmitoylation-modified proteomics, site-directed mutagenesis of palmitoylation sites, Western blot for ER stress markers\",\n      \"journal\": \"Journal of ovarian research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, mutagenesis with protein-level readout but no biochemical confirmation of palmitoylation site by acyl-RAC or ABE assay\",\n      \"pmids\": [\"41845436\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEC63 is an ER transmembrane J-domain co-chaperone that associates with the SEC61 protein-conducting channel (together with SEC62) to form the post-translational translocon; structurally, SEC63 induces partial opening of the SEC61 lateral gate while SEC62 displaces the plug domain to fully activate the channel for translocation of substrates bearing slowly gating or suboptimal signal peptides; SEC63 cooperates with BiP/KAR2 via its J-domain for client delivery, is phosphorylated by CK2 to enhance SEC62 binding, and in addition to its canonical translocation role, SEC63 regulates the IRE1α-XBP1 branch of the UPR, exists in a complex with polycystin-1, and is required for GPS cleavage and maturation of polycystin-1, thereby suppressing polycystic disease.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SEC63 is an ER-resident transmembrane J-domain co-chaperone that partners with SEC61 and SEC62 to form the post-translational protein translocation channel, and additionally facilitates co-translational import of precursors bearing slowly gating or suboptimal signal peptides [PMID:10799540, PMID:22375059, PMID:32133789]. Cryo-EM structures show that SEC63 induces partial opening of the SEC61 lateral gate through cytosolic and luminal domain contacts, while its J-domain recruits BiP/Kar2 to drive substrate translocation; CK2-mediated phosphorylation of SEC63 enhances SEC62 binding to complete channel activation [PMID:33398175, PMID:8305736, PMID:23287549]. Beyond translocation, SEC63 deficiency selectively activates the IRE1α–XBP1 branch of the UPR and impairs GPS cleavage and maturation of polycystin-1, linking SEC63 to polycystic kidney and liver disease [PMID:25844898, PMID:30745418]. Loss-of-function mutations in SEC63 cause autosomal dominant polycystic liver disease in humans [PMID:15133510].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing that SEC63 functionally cooperates with the ER luminal Hsp70 chaperone Kar2/BiP resolved how the J-domain of an ER translocon component couples to a chaperone motor for substrate translocation.\",\n      \"evidence\": \"Allele-specific suppression, synthetic lethality, and Northern blot in yeast sec63/kar2 mutants\",\n      \"pmids\": [\"8305736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical contact between SEC63 J-domain and Kar2 was inferred genetically, not shown biochemically in this study\", \"Whether SEC63–Kar2 cooperation extends to co-translational substrates was not tested\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Identification of SEC66/HSS1 and SON1–SON5 as suppressors of sec63 alleles expanded the translocon to additional subunits and hinted at SEC63 roles beyond secretory protein import.\",\n      \"evidence\": \"High-copy and extragenic suppressor screens in yeast, translocation precursor accumulation assays\",\n      \"pmids\": [\"8257794\", \"8514125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis of SON1-mediated suppression of sec63 was not determined\", \"Whether SEC66 is a stable stoichiometric subunit or regulatory factor was unclear\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating that mammalian SEC63 forms a ribosome-free complex with SEC61 and SEC62 established the existence of a dedicated post-translational translocon in the mammalian ER, resolving whether yeast findings were conserved.\",\n      \"evidence\": \"Biochemical fractionation and co-immunoprecipitation from mammalian ER membranes\",\n      \"pmids\": [\"10799540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate identity for the mammalian SEC62/SEC63 translocon was unknown\", \"Structural organization of the complex was not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying SEC63 loss-of-function mutations as the genetic cause of autosomal dominant polycystic liver disease linked ER translocation machinery to organ-level cystic pathology for the first time.\",\n      \"evidence\": \"Genetic mapping and mutation sequencing in affected human families\",\n      \"pmids\": [\"15133510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which SEC63-dependent client protein(s) are responsible for cystogenesis was unknown\", \"Whether haploinsufficiency or a two-hit mechanism drives disease was not established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"siRNA studies distinguished SEC63 from SEC62 substrate specificity: SEC63 is required for co-translational transport of specific signal-peptide precursors, not solely post-translational substrates, broadening its functional scope.\",\n      \"evidence\": \"siRNA knockdown in HeLa cells with semi-permeabilized cell translocation assays for multiple defined substrates\",\n      \"pmids\": [\"22375059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal peptide features that determine SEC63 dependence were not yet defined\", \"Whether BiP/J-domain interaction is required for the co-translational role was not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapping CK2-mediated phosphorylation of SEC63 at S574, S576, and S748 and showing it enhances SEC62 binding revealed a post-translational regulatory mechanism for translocon assembly.\",\n      \"evidence\": \"In vitro kinase assays, pull-down and co-immunoprecipitation in human cells\",\n      \"pmids\": [\"23287549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo phosphorylation dynamics and whether CK2 activity is regulated under ER stress were not examined\", \"Functional consequence of phosphorylation on translocation efficiency was not directly measured\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showing that SEC63 deficiency selectively activates the IRE1α–XBP1 UPR branch and that SEC63 complexes with polycystin-1 to regulate its GPS cleavage provided a mechanistic link from the translocon to cystic disease pathogenesis.\",\n      \"evidence\": \"Conditional knockout mice, co-immunoprecipitation, PC1 GPS cleavage assay, in vivo XBP1s rescue\",\n      \"pmids\": [\"25844898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SEC63 physically promotes GPS cleavage of PC1 was not resolved\", \"Whether the SEC63–PC1 interaction is direct or mediated by the translocon complex was not determined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that combined loss of SEC63 and IRE1α/XBP1 in collecting duct causes kidney injury rescuable by XBP1s established that basal UPR compensates for SEC63 loss to maintain renal proteostasis.\",\n      \"evidence\": \"Collecting duct–specific conditional knockout mice with functional and histological phenotyping, XBP1s re-expression rescue\",\n      \"pmids\": [\"30745418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the critical XBP1 target genes that compensate for SEC63 loss was not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Unbiased proteomic identification of SEC62/SEC63-dependent substrates and signal peptide mutagenesis defined the biochemical rules — long but less hydrophobic H-regions and downstream positive charges — that create SEC63 dependence, explaining substrate selectivity.\",\n      \"evidence\": \"Proteomics in intact human cells, in vitro translocation, signal peptide mutagenesis\",\n      \"pmids\": [\"32133789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these rules apply universally across cell types and species was not tested\", \"Structural basis for how suboptimal signal peptides engage SEC63-activated SEC61 was unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Cryo-EM structures of the SEC61–SEC62–SEC63 complex revealed that SEC63 partially opens the SEC61 lateral gate while SEC62 displaces the plug, providing an atomic-level mechanism for how the auxiliary translocon activates the channel.\",\n      \"evidence\": \"Cryo-EM at near-atomic resolution, molecular dynamics simulations, mutagenesis of contact residues in yeast\",\n      \"pmids\": [\"33398175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures of the complex engaged with a translocating substrate are lacking\", \"How BiP/J-domain action is coordinated with gate opening at the structural level remains unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that IRE1α phosphorylates SEC63 at T537 under ER stress, promoting ACLY stabilization and nuclear translocation to drive lipid biosynthesis and epigenetic activation of Snail1, suggested a non-canonical role for SEC63 in cancer metastasis.\",\n      \"evidence\": \"GST pull-down, IP-MS, phosphorylation/ubiquitination assays, RNA-seq, metabolite detection in HCC cell lines\",\n      \"pmids\": [\"37122003\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear translocation of an ER transmembrane protein lacks mechanistic explanation for membrane release\", \"Whether the SEC63–ACLY axis operates outside hepatocellular carcinoma contexts is unknown\", \"Independent replication is needed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of SEC63 J-domain–BiP coupling during active translocation, the direct versus indirect nature of the SEC63–polycystin-1 interaction, and whether SEC63 phosphorylation and palmitoylation integrate to tune translocon activity under physiological stress.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of the active SEC63–BiP–substrate ternary complex exists\", \"Palmitoylation of SEC63 at C490 has not been validated by orthogonal acyl-capture assays\", \"Two-hit versus haploinsufficiency mechanism in PCLD remains genetically unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [1, 9, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 15, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 5, 8, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0009536\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 8, 15, 16]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 8, 9, 15]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 12, 14]}\n    ],\n    \"complexes\": [\n      \"SEC61-SEC62-SEC63 translocon\",\n      \"SEC62/SEC63 post-translational translocon\"\n    ],\n    \"partners\": [\n      \"SEC61A1\",\n      \"SEC62\",\n      \"SEC66\",\n      \"SEC72\",\n      \"HSPA5\",\n      \"PKD1\",\n      \"CSNK2A1\",\n      \"ACLY\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}