{"gene":"SEC63","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2000,"finding":"Mammalian SEC63 associates with SEC61 and SEC62 in the ER membrane, forming a ribosome-free Sec61-Sec62-Sec63 complex; SEC63 is the mammalian homolog of yeast Sec63p based on primary sequence analysis.","method":"Biochemical fractionation, primary sequence analysis, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-immunoprecipitation identifying the complex, single lab, direct biochemical demonstration","pmids":["10799540"],"is_preprint":false},{"year":1993,"finding":"Yeast Sec63p (DnaJ homolog) genetically interacts with Kar2p (BiP/DnaK homolog) in ER protein translocation: temperature-sensitive KAR2 mutations are synthetically lethal with sec63 mutations, dominant KAR2 mutations allele-specifically suppress sec63-1, and sec63-1 induces KAR2 mRNA, indicating the two proteins interact functionally during translocation analogously to DnaK-DnaJ.","method":"Yeast genetic epistasis, synthetic lethality, allele-specific suppression, Northern blot","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic approaches (synthetic lethality, allele-specific suppression, mRNA induction) establishing functional interaction in vivo","pmids":["8305736"],"is_preprint":false},{"year":1993,"finding":"Suppressor screen of sec63-101 (yeast) identified SON1, a nuclear protein whose loss suppresses sec63 mutations, placing SEC63 in a pathway involving nuclear protein localization in addition to ER translocation.","method":"Extragenic suppressor screen, genetic complementation, gene mapping","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via suppressor screen, single lab, functionally validated by phenotypic analyses","pmids":["8514125"],"is_preprint":false},{"year":1993,"finding":"High-copy suppression of sec63-101 identified HSS1/SEC66, an integral ER membrane glycoprotein that is complexed with Sec62p and Sec63p and required for ER translocation; hss1 null alleles cause accumulation of translocation precursors and are synthetically lethal with other translocation mutants.","method":"High-copy suppressor cloning, gene disruption, pulse-chase translocation assay, synthetic lethality","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic suppression, biochemical complex identification, translocation assay; single lab","pmids":["8257794"],"is_preprint":false},{"year":2003,"finding":"Yeast Sec62p and Sec63p interact directly at the cytosolic surface of the ER; subdomains of each protein mediating the interaction were mapped, and Sec72p was found to homodimerize.","method":"Yeast two-hybrid, pull-down assays, domain mapping","journal":"Yeast (Chichester, England)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct pull-down and yeast two-hybrid, multiple interaction pairs tested, single lab","pmids":["12518317"],"is_preprint":false},{"year":2004,"finding":"Loss-of-function mutations in SEC63, encoding a component of the ER protein translocation machinery, cause autosomal dominant polycystic liver disease in humans, implicating cotranslational protein-processing pathways in maintaining epithelial luminal structure.","method":"Human genetic linkage and mutation analysis, sequencing","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — causative mutations identified in multiple independent families, disease mechanism established; widely replicated","pmids":["15133510"],"is_preprint":false},{"year":2012,"finding":"Knockdown of SEC63 in human HeLa cells inhibits co-translational transport of specific signal-peptide-containing precursor proteins into the ER in a precursor-specific manner, while SEC62 knockdown inhibits only post-translational transport.","method":"siRNA knockdown, semi-permeabilized cell transport assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockdown with defined substrate-specific transport phenotypes, two orthogonal knockdown targets compared","pmids":["22375059"],"is_preprint":false},{"year":2012,"finding":"CK2 phosphorylates human SEC63 at serine residues 574, 576, and 748; phosphorylation of SEC63 by CK2 enhances its binding to SEC62, and SEC63 was identified as a novel substrate/binding partner of CK2.","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 / Moderate — in vitro phosphorylation site mapping plus co-IP functional consequence; single lab, two orthogonal methods","pmids":["23287549"],"is_preprint":false},{"year":2012,"finding":"Overexpression of human SEC63 selectively reduces steady-state levels of multi-spanning (polytopic) membrane proteins in a co-translational mode, while knockdown increases their levels; a J-domain mutation in SEC63 reduces this effect, implicating BiP recruitment in SEC63-mediated quantity control of polytopic ER proteins.","method":"Overexpression and siRNA knockdown in human cell lines, Western blot, J-domain mutagenesis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined substrate class phenotype plus mutagenesis; single lab","pmids":["23166619"],"is_preprint":false},{"year":2011,"finding":"Human SEC63 interacts with the cytosolic protein nucleoredoxin (NRX), an interaction identified by yeast two-hybrid screening and characterized biochemically, linking SEC63 to Wnt signaling pathways.","method":"Yeast two-hybrid screen, biochemical interaction characterization","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid identification plus limited follow-up, single lab, single method type","pmids":["21251912"],"is_preprint":false},{"year":2015,"finding":"SEC63 deficiency in mice selectively activates the IRE1α-XBP1 branch of the unfolded protein response; SEC63 exists in a complex with polycystin-1 (PC1); loss of both SEC63 and XBP1 markedly suppresses GPS cleavage of PC1; enforced expression of spliced XBP1 enhances GPS cleavage of PC1 in SEC63-deficient cells.","method":"Murine genetic models (conditional knockout), co-immunoprecipitation, in vivo XBP1 overexpression rescue, PC1 GPS cleavage assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (genetic epistasis, co-IP, rescue experiments) in vivo and in vitro; single lab but rigorous and comprehensive","pmids":["25844898"],"is_preprint":false},{"year":2014,"finding":"Mutations in the N-terminal cytosolic domain of yeast Sec62 impair its interaction with Sec63 and cause defects in membrane insertion and C-terminus translocation of single- and multi-spanning membrane proteins, revealing a function for the Sec62-Sec63 translocon in membrane protein topogenesis.","method":"Yeast mutagenesis, co-immunoprecipitation, metabolic labeling translocation assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutation analysis combined with translocation assays; single lab, two methods","pmids":["25097231"],"is_preprint":false},{"year":2019,"finding":"The N-terminal 39 residues of yeast Sec63 are required for stability of the SEC complex (Sec61 plus Sec62/Sec63) and for proper insertion/topogenesis of single- and double-pass membrane proteins in vivo.","method":"N-terminal deletion mutagenesis in yeast, Blue-Native PAGE, 5-min metabolic labeling translocation assay","journal":"Biochimica et biophysica acta. General subjects","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with BN-PAGE and metabolic labeling, two orthogonal methods; single lab","pmids":["31195072"],"is_preprint":false},{"year":2020,"finding":"Human Sec62/Sec63 complex supports ER import of substrates with signal peptides having longer but less hydrophobic hydrophobic regions and lower C-region polarity; substrates with slowly gating signal peptides and downstream positively charged clusters require both Sec62/Sec63 and BiP for translocation, and these features correlate with sensitivity to the Sec61 inhibitor CAM741.","method":"Unbiased proteomics (in intact human cells with siRNA knockdown), in vitro translocation assay, signal peptide mutagenesis","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — unbiased proteomics screen in intact cells combined with mechanistic signal peptide mutagenesis and in vitro translocation assays; single lab with multiple orthogonal approaches","pmids":["32133789"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structures of Sec61-Sec62-Sec63 complexes from S. cerevisiae and T. lanuginosus show that Sec63 and Sec62 cooperatively open the Sec61 channel in a stepwise manner: Sec63 first partially opens the Sec61 lateral gate via cytosolic and luminal domain contacts, then Sec62 displaces the plug domain to open the translocation pore; without Sec62 the pore remains closed.","method":"Cryo-electron microscopy structure determination, molecular dynamics simulations, mutagenesis of Sec61-Sec63 contact interfaces","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures at multiple states, MD simulations, and interface mutagenesis together establish the stepwise gating mechanism","pmids":["33398175"],"is_preprint":false},{"year":2021,"finding":"Molecular dynamics simulations and co-precipitation from yeast show that Sec63 influences the conformation of the Sec61 lateral gate, plug, pore region, and pore ring diameter through three intermolecular contact regions; Sbh1 (the β subunit of Sec61) is not required for stable Sec63-Sec61 contacts.","method":"Molecular dynamics simulations, co-precipitation assay, molecular docking","journal":"PLoS computational biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-precipitation (experimental) combined with MD simulation; single lab","pmids":["33780447"],"is_preprint":false},{"year":2019,"finding":"In mice, inactivation of Sec63 in collecting ducts together with inactivation of XBP1 or IRE1α causes interstitial inflammation and fibrosis; re-expression of spliced XBP1 completely rescues this phenotype, demonstrating that basal IRE1α-XBP1 activity is required to maintain proteostasis in the absence of Sec63.","method":"Conditional knockout mouse genetics, in vivo XBP1s rescue, kidney function assays, histology","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 / Strong — double conditional knockout plus in vivo rescue demonstrates epistatic relationship, multiple phenotypic endpoints","pmids":["30745418"],"is_preprint":false},{"year":2021,"finding":"SOX9 transcriptionally regulates SEC63 expression in biliary epithelial cells as demonstrated by chromatin immunoprecipitation and luciferase reporter assays; overexpression of SEC63 partially reverses SOX9-depletion-induced loss of primary cilia and increased cell proliferation.","method":"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, siRNA knockdown, SEC63 overexpression rescue","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter provide direct evidence of transcriptional regulation; rescue experiment links SEC63 to ciliogenesis; single lab","pmids":["33512716"],"is_preprint":false},{"year":2023,"finding":"Upon ER stress, IRE1α-mediated phosphorylation of SEC63 at T537 activates SEC63; activated SEC63 stabilizes ACLY to increase acetyl-CoA and lipid biosynthesis; SEC63 also translocates to the nucleus to increase nuclear acetyl-CoA and upregulate UPR targets; SEC63 cooperates with ACLY to epigenetically upregulate Snail1, promoting HCC metastasis.","method":"GST pull-down, co-immunoprecipitation/mass spectrometry, in vivo ubiquitination/phosphorylation assay, RNA-sequencing, metabolites detection, immunofluorescence, transwell migration/invasion assays","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods (pull-down, IP-MS, phosphorylation assay) in single lab; functional rescue experiments performed","pmids":["37122003"],"is_preprint":false},{"year":2010,"finding":"Yeast Hph1 and Hph2 interact with Sec71, Sec72, Sec62, and Sec63 as components of the Sec63/Sec62 post-translational translocation complex; loss of Hph1/Hph2 phenocopies sec71Δ in reducing vacuolar acidification and Vph1 stability, placing Hph1/Hph2 in the Sec63/Sec62 complex for V-ATPase biogenesis.","method":"Split-ubiquitin membrane yeast two-hybrid, genetic epistasis, vacuolar acidification assay, Western blot for Vph1 stability","journal":"Eukaryotic cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein interaction screen plus genetic epistasis with defined biochemical phenotype; single lab","pmids":["21097665"],"is_preprint":false},{"year":2012,"finding":"In zebrafish sec63 mutants, loss of Sec63 causes swollen ER in myelinating glia, upregulation of ER stress markers, reduced voltage-gated sodium channel clustering at nodes of Ranvier, and liver ER fragmentation/swelling, demonstrating that Sec63 is required for ER proteostasis in myelinating glia and hepatocytes in vivo.","method":"Zebrafish genetic mutant characterization, immunofluorescence, electron microscopy, in situ hybridization for ER stress markers","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with multiple cellular phenotypes and defined molecular consequences; single lab","pmids":["22864019"],"is_preprint":false},{"year":2026,"finding":"Palmitoylation of SEC63 at residue C490 by palmitic acid promotes ER stress; mutation of this palmitoylation site (SEC63-C490) significantly reduces GRP78, CHOP, and ATF6 expression (~70%, ~60%, ~50% respectively), demonstrating that palmitoylation modification of SEC63 mediates palmitic acid-induced ER stress in ovarian granulosa cells.","method":"Palmitoylation-modified proteomics, site-directed mutagenesis (C490), Western blot for ER stress markers","journal":"Journal of ovarian research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics identification of palmitoylation site plus mutagenesis with quantitative ER stress readouts; single lab","pmids":["41845436"],"is_preprint":false}],"current_model":"SEC63 encodes an ER transmembrane HSP40/DnaJ-domain cochaperone that associates with the SEC61 protein-conducting channel and SEC62 to form the Sec61-Sec62-Sec63 translocon complex; structurally, Sec63 first partially opens the Sec61 lateral gate via cytosolic and luminal contacts, enabling Sec62 to displace the plug and fully open the pore for post-translational (and some co-translational, substrate-specific) protein import; SEC63 physically complexes with polycystin-1 (PC1) and with BiP via its J domain, is phosphorylated by CK2 (enhancing SEC62 binding) and by IRE1α (activating SEC63 during ER stress), and activates the IRE1α-XBP1 branch of the UPR when lost—a protective response required for PC1 GPS cleavage and epithelial proteostasis; loss-of-function mutations in humans cause autosomal dominant polycystic liver disease through a two-hit mechanism reducing PC1 biogenesis."},"narrative":{"mechanistic_narrative":"SEC63 encodes an ER transmembrane HSP40/DnaJ-domain cochaperone that is a core subunit of the post-translational protein-conducting machinery, associating with the SEC61 channel and SEC62 in a ribosome-free Sec61-Sec62-Sec63 complex [PMID:10799540]. Functionally, Sec63 partners with the BiP/Kar2p chaperone—genetically established in yeast through synthetic lethality, allele-specific suppression, and reciprocal mRNA induction analogous to a DnaK-DnaJ pair [PMID:8305736]—and its J domain recruits BiP to drive substrate translocation and quantity control of polytopic ER membrane proteins [PMID:23166619]. Cryo-EM structures resolve the activation mechanism: Sec63 first partially opens the Sec61 lateral gate through cytosolic and luminal domain contacts, after which Sec62 displaces the plug to fully open the translocation pore [PMID:33398175, PMID:33780447]. SEC63 governs substrate-specific import, supporting co-translational transport of particular signal-peptide precursors and, together with BiP, translocation of substrates bearing slowly gating signal peptides and downstream positive-charge clusters [PMID:22375059, PMID:32133789], and is required for membrane protein topogenesis [PMID:25097231, PMID:31195072]. Beyond translocation, SEC63 exists in a complex with polycystin-1 (PC1), and its loss selectively activates the protective IRE1α-XBP1 branch of the unfolded protein response needed for PC1 GPS cleavage and epithelial proteostasis [PMID:25844898, PMID:30745418]. Loss-of-function mutations in SEC63 cause autosomal dominant polycystic liver disease in humans [PMID:15133510]. SEC63 activity is tuned by post-translational modification, including CK2 phosphorylation that enhances SEC62 binding [PMID:23287549] and IRE1α-mediated phosphorylation during ER stress [PMID:37122003].","teleology":[{"year":1993,"claim":"Established that Sec63 acts functionally as a DnaJ-type cochaperone for the BiP/Kar2p chaperone during ER translocation, defining the chaperone logic of the machinery.","evidence":"Yeast genetic epistasis, synthetic lethality, allele-specific suppression, and Northern blot in S. cerevisiae","pmids":["8305736"],"confidence":"High","gaps":["Genetic interaction did not resolve which translocation step BiP recruitment drives","No direct biochemical reconstitution of the Sec63 J-domain/BiP cycle"]},{"year":1993,"claim":"Suppressor and high-copy screens placed SEC63 in a defined translocation complex (with Sec66/Hss1) and linked it to nuclear protein localization, broadening its functional context.","evidence":"Extragenic and high-copy suppressor screens, gene disruption, and pulse-chase translocation assays in yeast","pmids":["8514125","8257794"],"confidence":"Medium","gaps":["Mechanistic basis of the SON1/nuclear-localization connection unresolved","Stoichiometry of Sec66 within the complex not defined"]},{"year":2000,"claim":"Demonstrated that the yeast translocation logic is conserved in mammals by identifying a ribosome-free SEC61-SEC62-SEC63 complex in the ER membrane.","evidence":"Biochemical fractionation, primary sequence analysis, and reciprocal co-immunoprecipitation in mammalian ER","pmids":["10799540"],"confidence":"Medium","gaps":["Did not define substrate selectivity of the mammalian complex","Subunit stoichiometry and architecture unresolved"]},{"year":2003,"claim":"Mapped the direct Sec62-Sec63 interaction at the ER cytosolic surface, defining how the regulatory subunits physically engage.","evidence":"Yeast two-hybrid, pull-down assays, and domain mapping","pmids":["12518317"],"confidence":"Medium","gaps":["Interaction mapped in yeast, not validated for human orthologs at the time","Did not connect interface to channel gating"]},{"year":2004,"claim":"Connected the translocation machinery to human disease by showing SEC63 loss-of-function mutations cause autosomal dominant polycystic liver disease.","evidence":"Human genetic linkage, mutation analysis, and sequencing across families","pmids":["15133510"],"confidence":"High","gaps":["Did not establish the molecular pathway from translocation defect to cyst formation","Two-hit cellular mechanism not yet defined"]},{"year":2012,"claim":"Defined SEC63's substrate-specific role in human cells, distinguishing it from SEC62 and linking its J domain (BiP recruitment) to quantity control of polytopic membrane proteins.","evidence":"siRNA knockdown/overexpression, semi-permeabilized and intact-cell transport assays, J-domain mutagenesis, and CK2 phosphorylation site mapping in human cells","pmids":["22375059","23166619","23287549"],"confidence":"Medium","gaps":["Substrate selection rules only partially defined","Functional consequence of CK2 phosphorylation beyond enhanced SEC62 binding unclear"]},{"year":2014,"claim":"Established that the Sec62-Sec63 translocon functions in membrane protein topogenesis, not just soluble protein import, and that the Sec63 N-terminus stabilizes the assembled SEC complex.","evidence":"Yeast mutagenesis, N-terminal deletion, co-IP, Blue-Native PAGE, and metabolic-labeling translocation assays","pmids":["25097231","31195072"],"confidence":"Medium","gaps":["Mechanistic coupling of complex stability to topogenesis not structurally resolved","Findings derived from yeast"]},{"year":2015,"claim":"Revealed that SEC63 loss is buffered by selective IRE1α-XBP1 UPR activation required for PC1 GPS cleavage, defining the protective pathway underlying the disease mechanism.","evidence":"Conditional knockout mice, co-IP of the SEC63-PC1 complex, XBP1 epistasis, and PC1 GPS cleavage rescue assays","pmids":["25844898","30745418"],"confidence":"High","gaps":["How SEC63 loss is sensed to activate IRE1α not defined","Direct biochemical role of SEC63 in PC1 maturation unresolved"]},{"year":2020,"claim":"Defined the biophysical signal-peptide features that route substrates to the SEC62/SEC63/BiP-dependent import pathway, explaining its substrate selectivity.","evidence":"Unbiased proteomics with siRNA knockdown in intact cells, in vitro translocation, and signal-peptide mutagenesis","pmids":["32133789"],"confidence":"High","gaps":["Quantitative contribution of each signal-peptide feature not fully separated","BiP requirement defined for a substrate subset only"]},{"year":2021,"claim":"Provided the structural mechanism of channel activation, showing Sec63 partially opens the Sec61 lateral gate via three contact regions and licenses Sec62 to displace the plug and open the pore.","evidence":"Cryo-EM of Sec61-Sec62-Sec63 complexes from two species, molecular dynamics simulations, co-precipitation, and interface mutagenesis","pmids":["33398175","33780447"],"confidence":"High","gaps":["Captured states do not include an engaged translocating substrate","Conformational role of post-translational modifications in gating not addressed"]},{"year":2021,"claim":"Placed SEC63 downstream of SOX9 transcriptional control and linked its expression to primary cilium maintenance in biliary epithelium.","evidence":"ChIP, luciferase reporter assays, siRNA knockdown, and SEC63 overexpression rescue","pmids":["33512716"],"confidence":"Medium","gaps":["Mechanism linking SEC63 levels to ciliogenesis unresolved","Single-lineage cell context"]},{"year":2023,"claim":"Extended SEC63 function beyond the ER, showing IRE1α phosphorylation activates a SEC63-ACLY axis driving acetyl-CoA/lipid metabolism, nuclear UPR target induction, and HCC metastasis.","evidence":"GST pull-down, co-IP/mass spectrometry, phosphorylation and ubiquitination assays, RNA-seq, metabolite detection, and migration/invasion assays","pmids":["37122003"],"confidence":"Medium","gaps":["Nuclear translocation mechanism of an ER membrane protein not defined","Generality beyond HCC unestablished"]},{"year":2026,"claim":"Identified palmitoylation as a lipid-responsive modification of SEC63 that promotes ER stress, linking metabolic input to SEC63-dependent stress signaling.","evidence":"Palmitoylation proteomics, C490 site-directed mutagenesis, and Western blot for ER stress markers in ovarian granulosa cells","pmids":["41845436"],"confidence":"Medium","gaps":["Enzyme catalyzing SEC63 palmitoylation not identified","Mechanistic link between palmitoylation and downstream stress effectors undefined"]},{"year":null,"claim":"How SEC63's diverse post-translational modifications (CK2, IRE1α, palmitoylation) and non-ER (nuclear) functions integrate with its translocation cochaperone role to control proteostasis and disease remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coupling channel gating to modification state","Substrate-level basis of PCLD pathogenesis not fully reconstituted"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[1,8]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,14]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,4,20]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[18]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,6,13]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[6,11,13]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[10,16,21]}],"complexes":["Sec61-Sec62-Sec63 translocon complex","SEC63-polycystin-1 (PC1) complex"],"partners":["SEC61","SEC62","BIP/KAR2P","SEC66/HSS1","POLYCYSTIN-1 (PC1)","CK2","IRE1Α","ACLY"],"other_free_text":[]}},"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":196,"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":140,"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":134,"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":"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":52,"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":52,"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":"16835903","id":"PMC_16835903","title":"Extensive mutational analysis of PRKCSH and SEC63 broadens the spectrum of polycystic liver disease.","date":"2006","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/16835903","citation_count":46,"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 journal","url":"https://pubmed.ncbi.nlm.nih.gov/32133789","citation_count":46,"is_preprint":false},{"pmid":"8257794","id":"PMC_8257794","title":"Suppression of a sec63 mutation identifies a novel component of the yeast endoplasmic reticulum translocation apparatus.","date":"1993","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/8257794","citation_count":43,"is_preprint":false},{"pmid":"20095989","id":"PMC_20095989","title":"Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63.","date":"2010","source":"Clinical 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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":"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":"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":"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":"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":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":"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":3,"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":"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":"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":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":20671,"output_tokens":5038,"usd":0.068792,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13457,"output_tokens":4261,"usd":0.086905,"stage2_stop_reason":"end_turn"},"total_usd":0.155697,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Mammalian SEC63 associates with SEC61 and SEC62 in the ER membrane, forming a ribosome-free Sec61-Sec62-Sec63 complex; SEC63 is the mammalian homolog of yeast Sec63p based on primary sequence analysis.\",\n      \"method\": \"Biochemical fractionation, primary sequence analysis, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-immunoprecipitation identifying the complex, single lab, direct biochemical demonstration\",\n      \"pmids\": [\"10799540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Yeast Sec63p (DnaJ homolog) genetically interacts with Kar2p (BiP/DnaK homolog) in ER protein translocation: temperature-sensitive KAR2 mutations are synthetically lethal with sec63 mutations, dominant KAR2 mutations allele-specifically suppress sec63-1, and sec63-1 induces KAR2 mRNA, indicating the two proteins interact functionally during translocation analogously to DnaK-DnaJ.\",\n      \"method\": \"Yeast genetic epistasis, synthetic lethality, allele-specific suppression, Northern blot\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic approaches (synthetic lethality, allele-specific suppression, mRNA induction) establishing functional interaction in vivo\",\n      \"pmids\": [\"8305736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Suppressor screen of sec63-101 (yeast) identified SON1, a nuclear protein whose loss suppresses sec63 mutations, placing SEC63 in a pathway involving nuclear protein localization in addition to ER translocation.\",\n      \"method\": \"Extragenic suppressor screen, genetic complementation, gene mapping\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via suppressor screen, single lab, functionally validated by phenotypic analyses\",\n      \"pmids\": [\"8514125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"High-copy suppression of sec63-101 identified HSS1/SEC66, an integral ER membrane glycoprotein that is complexed with Sec62p and Sec63p and required for ER translocation; hss1 null alleles cause accumulation of translocation precursors and are synthetically lethal with other translocation mutants.\",\n      \"method\": \"High-copy suppressor cloning, gene disruption, pulse-chase translocation assay, synthetic lethality\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic suppression, biochemical complex identification, translocation assay; single lab\",\n      \"pmids\": [\"8257794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Yeast Sec62p and Sec63p interact directly at the cytosolic surface of the ER; subdomains of each protein mediating the interaction were mapped, and Sec72p was found to homodimerize.\",\n      \"method\": \"Yeast two-hybrid, pull-down assays, domain mapping\",\n      \"journal\": \"Yeast (Chichester, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct pull-down and yeast two-hybrid, multiple interaction pairs tested, single lab\",\n      \"pmids\": [\"12518317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Loss-of-function mutations in SEC63, encoding a component of the ER protein translocation machinery, cause autosomal dominant polycystic liver disease in humans, implicating cotranslational protein-processing pathways in maintaining epithelial luminal structure.\",\n      \"method\": \"Human genetic linkage and mutation analysis, sequencing\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — causative mutations identified in multiple independent families, disease mechanism established; widely replicated\",\n      \"pmids\": [\"15133510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Knockdown of SEC63 in human HeLa cells inhibits co-translational transport of specific signal-peptide-containing precursor proteins into the ER in a precursor-specific manner, while SEC62 knockdown inhibits only post-translational transport.\",\n      \"method\": \"siRNA knockdown, semi-permeabilized cell transport assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockdown with defined substrate-specific transport phenotypes, two orthogonal knockdown targets compared\",\n      \"pmids\": [\"22375059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CK2 phosphorylates human SEC63 at serine residues 574, 576, and 748; phosphorylation of SEC63 by CK2 enhances its binding to SEC62, and SEC63 was identified as a novel substrate/binding partner of CK2.\",\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 / Moderate — in vitro phosphorylation site mapping plus co-IP functional consequence; single lab, two orthogonal methods\",\n      \"pmids\": [\"23287549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Overexpression of human SEC63 selectively reduces steady-state levels of multi-spanning (polytopic) membrane proteins in a co-translational mode, while knockdown increases their levels; a J-domain mutation in SEC63 reduces this effect, implicating BiP recruitment in SEC63-mediated quantity control of polytopic ER proteins.\",\n      \"method\": \"Overexpression and siRNA knockdown in human cell lines, Western blot, J-domain mutagenesis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined substrate class phenotype plus mutagenesis; single lab\",\n      \"pmids\": [\"23166619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human SEC63 interacts with the cytosolic protein nucleoredoxin (NRX), an interaction identified by yeast two-hybrid screening and characterized biochemically, linking SEC63 to Wnt signaling pathways.\",\n      \"method\": \"Yeast two-hybrid screen, biochemical interaction characterization\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid identification plus limited follow-up, single lab, single method type\",\n      \"pmids\": [\"21251912\"],\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; SEC63 exists in a complex with polycystin-1 (PC1); loss of both SEC63 and XBP1 markedly suppresses GPS cleavage of PC1; enforced expression of spliced XBP1 enhances GPS cleavage of PC1 in SEC63-deficient cells.\",\n      \"method\": \"Murine genetic models (conditional knockout), co-immunoprecipitation, in vivo XBP1 overexpression rescue, PC1 GPS cleavage assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (genetic epistasis, co-IP, rescue experiments) in vivo and in vitro; single lab but rigorous and comprehensive\",\n      \"pmids\": [\"25844898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mutations in the N-terminal cytosolic domain of yeast Sec62 impair its interaction with Sec63 and cause defects in membrane insertion and C-terminus translocation of single- and multi-spanning membrane proteins, revealing a function for the Sec62-Sec63 translocon in membrane protein topogenesis.\",\n      \"method\": \"Yeast mutagenesis, co-immunoprecipitation, metabolic labeling translocation assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutation analysis combined with translocation assays; single lab, two methods\",\n      \"pmids\": [\"25097231\"],\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 plus Sec62/Sec63) and for proper insertion/topogenesis of single- and double-pass membrane proteins in vivo.\",\n      \"method\": \"N-terminal deletion mutagenesis in yeast, Blue-Native PAGE, 5-min metabolic labeling translocation assay\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with BN-PAGE and metabolic labeling, two orthogonal methods; single lab\",\n      \"pmids\": [\"31195072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human Sec62/Sec63 complex supports ER import of substrates with signal peptides having longer but less hydrophobic hydrophobic regions and lower C-region polarity; substrates with slowly gating signal peptides and downstream positively charged clusters require both Sec62/Sec63 and BiP for translocation, and these features correlate with sensitivity to the Sec61 inhibitor CAM741.\",\n      \"method\": \"Unbiased proteomics (in intact human cells with siRNA knockdown), in vitro translocation assay, signal peptide mutagenesis\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — unbiased proteomics screen in intact cells combined with mechanistic signal peptide mutagenesis and in vitro translocation assays; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"32133789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structures of Sec61-Sec62-Sec63 complexes from S. cerevisiae and T. lanuginosus show that Sec63 and Sec62 cooperatively open the Sec61 channel in a stepwise manner: Sec63 first partially opens the Sec61 lateral gate via cytosolic and luminal domain contacts, then Sec62 displaces the plug domain to open the translocation pore; without Sec62 the pore remains closed.\",\n      \"method\": \"Cryo-electron microscopy structure determination, molecular dynamics simulations, mutagenesis of Sec61-Sec63 contact interfaces\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures at multiple states, MD simulations, and interface mutagenesis together establish the stepwise gating mechanism\",\n      \"pmids\": [\"33398175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Molecular dynamics simulations and co-precipitation from yeast show that Sec63 influences the conformation of the Sec61 lateral gate, plug, pore region, and pore ring diameter through three intermolecular contact regions; Sbh1 (the β subunit of Sec61) is not required for stable Sec63-Sec61 contacts.\",\n      \"method\": \"Molecular dynamics simulations, co-precipitation assay, molecular docking\",\n      \"journal\": \"PLoS computational biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-precipitation (experimental) combined with MD simulation; single lab\",\n      \"pmids\": [\"33780447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In mice, inactivation of Sec63 in collecting ducts together with inactivation of XBP1 or IRE1α causes interstitial inflammation and fibrosis; re-expression of spliced XBP1 completely rescues this phenotype, demonstrating that basal IRE1α-XBP1 activity is required to maintain proteostasis in the absence of Sec63.\",\n      \"method\": \"Conditional knockout mouse genetics, in vivo XBP1s rescue, kidney function assays, histology\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double conditional knockout plus in vivo rescue demonstrates epistatic relationship, multiple phenotypic endpoints\",\n      \"pmids\": [\"30745418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SOX9 transcriptionally regulates SEC63 expression in biliary epithelial cells as demonstrated by chromatin immunoprecipitation and luciferase reporter assays; overexpression of SEC63 partially reverses SOX9-depletion-induced loss of primary cilia and increased cell proliferation.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, siRNA knockdown, SEC63 overexpression rescue\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter provide direct evidence of transcriptional regulation; rescue experiment links SEC63 to ciliogenesis; single lab\",\n      \"pmids\": [\"33512716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Upon ER stress, IRE1α-mediated phosphorylation of SEC63 at T537 activates SEC63; activated SEC63 stabilizes ACLY to increase acetyl-CoA and lipid biosynthesis; SEC63 also translocates to the nucleus to increase nuclear acetyl-CoA and upregulate UPR targets; SEC63 cooperates with ACLY to epigenetically upregulate Snail1, promoting HCC metastasis.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation/mass spectrometry, in vivo ubiquitination/phosphorylation assay, RNA-sequencing, metabolites detection, immunofluorescence, transwell migration/invasion assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods (pull-down, IP-MS, phosphorylation assay) in single lab; functional rescue experiments performed\",\n      \"pmids\": [\"37122003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Yeast Hph1 and Hph2 interact with Sec71, Sec72, Sec62, and Sec63 as components of the Sec63/Sec62 post-translational translocation complex; loss of Hph1/Hph2 phenocopies sec71Δ in reducing vacuolar acidification and Vph1 stability, placing Hph1/Hph2 in the Sec63/Sec62 complex for V-ATPase biogenesis.\",\n      \"method\": \"Split-ubiquitin membrane yeast two-hybrid, genetic epistasis, vacuolar acidification assay, Western blot for Vph1 stability\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein interaction screen plus genetic epistasis with defined biochemical phenotype; single lab\",\n      \"pmids\": [\"21097665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In zebrafish sec63 mutants, loss of Sec63 causes swollen ER in myelinating glia, upregulation of ER stress markers, reduced voltage-gated sodium channel clustering at nodes of Ranvier, and liver ER fragmentation/swelling, demonstrating that Sec63 is required for ER proteostasis in myelinating glia and hepatocytes in vivo.\",\n      \"method\": \"Zebrafish genetic mutant characterization, immunofluorescence, electron microscopy, in situ hybridization for ER stress markers\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with multiple cellular phenotypes and defined molecular consequences; single lab\",\n      \"pmids\": [\"22864019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Palmitoylation of SEC63 at residue C490 by palmitic acid promotes ER stress; mutation of this palmitoylation site (SEC63-C490) significantly reduces GRP78, CHOP, and ATF6 expression (~70%, ~60%, ~50% respectively), demonstrating that palmitoylation modification of SEC63 mediates palmitic acid-induced ER stress in ovarian granulosa cells.\",\n      \"method\": \"Palmitoylation-modified proteomics, site-directed mutagenesis (C490), Western blot for ER stress markers\",\n      \"journal\": \"Journal of ovarian research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics identification of palmitoylation site plus mutagenesis with quantitative ER stress readouts; single lab\",\n      \"pmids\": [\"41845436\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEC63 encodes an ER transmembrane HSP40/DnaJ-domain cochaperone that associates with the SEC61 protein-conducting channel and SEC62 to form the Sec61-Sec62-Sec63 translocon complex; structurally, Sec63 first partially opens the Sec61 lateral gate via cytosolic and luminal contacts, enabling Sec62 to displace the plug and fully open the pore for post-translational (and some co-translational, substrate-specific) protein import; SEC63 physically complexes with polycystin-1 (PC1) and with BiP via its J domain, is phosphorylated by CK2 (enhancing SEC62 binding) and by IRE1α (activating SEC63 during ER stress), and activates the IRE1α-XBP1 branch of the UPR when lost—a protective response required for PC1 GPS cleavage and epithelial proteostasis; loss-of-function mutations in humans cause autosomal dominant polycystic liver disease through a two-hit mechanism reducing PC1 biogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEC63 encodes an ER transmembrane HSP40/DnaJ-domain cochaperone that is a core subunit of the post-translational protein-conducting machinery, associating with the SEC61 channel and SEC62 in a ribosome-free Sec61-Sec62-Sec63 complex [#0]. Functionally, Sec63 partners with the BiP/Kar2p chaperone—genetically established in yeast through synthetic lethality, allele-specific suppression, and reciprocal mRNA induction analogous to a DnaK-DnaJ pair [#1]—and its J domain recruits BiP to drive substrate translocation and quantity control of polytopic ER membrane proteins [#8]. Cryo-EM structures resolve the activation mechanism: Sec63 first partially opens the Sec61 lateral gate through cytosolic and luminal domain contacts, after which Sec62 displaces the plug to fully open the translocation pore [#14, #15]. SEC63 governs substrate-specific import, supporting co-translational transport of particular signal-peptide precursors and, together with BiP, translocation of substrates bearing slowly gating signal peptides and downstream positive-charge clusters [#6, #13], and is required for membrane protein topogenesis [#11, #12]. Beyond translocation, SEC63 exists in a complex with polycystin-1 (PC1), and its loss selectively activates the protective IRE1\\u03b1-XBP1 branch of the unfolded protein response needed for PC1 GPS cleavage and epithelial proteostasis [#10, #16]. Loss-of-function mutations in SEC63 cause autosomal dominant polycystic liver disease in humans [#5]. SEC63 activity is tuned by post-translational modification, including CK2 phosphorylation that enhances SEC62 binding [#7] and IRE1\\u03b1-mediated phosphorylation during ER stress [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established that Sec63 acts functionally as a DnaJ-type cochaperone for the BiP/Kar2p chaperone during ER translocation, defining the chaperone logic of the machinery.\",\n      \"evidence\": \"Yeast genetic epistasis, synthetic lethality, allele-specific suppression, and Northern blot in S. cerevisiae\",\n      \"pmids\": [\"8305736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genetic interaction did not resolve which translocation step BiP recruitment drives\", \"No direct biochemical reconstitution of the Sec63 J-domain/BiP cycle\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Suppressor and high-copy screens placed SEC63 in a defined translocation complex (with Sec66/Hss1) and linked it to nuclear protein localization, broadening its functional context.\",\n      \"evidence\": \"Extragenic and high-copy suppressor screens, gene disruption, and pulse-chase translocation assays in yeast\",\n      \"pmids\": [\"8514125\", \"8257794\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis of the SON1/nuclear-localization connection unresolved\", \"Stoichiometry of Sec66 within the complex not defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated that the yeast translocation logic is conserved in mammals by identifying a ribosome-free SEC61-SEC62-SEC63 complex in the ER membrane.\",\n      \"evidence\": \"Biochemical fractionation, primary sequence analysis, and reciprocal co-immunoprecipitation in mammalian ER\",\n      \"pmids\": [\"10799540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define substrate selectivity of the mammalian complex\", \"Subunit stoichiometry and architecture unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapped the direct Sec62-Sec63 interaction at the ER cytosolic surface, defining how the regulatory subunits physically engage.\",\n      \"evidence\": \"Yeast two-hybrid, pull-down assays, and domain mapping\",\n      \"pmids\": [\"12518317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction mapped in yeast, not validated for human orthologs at the time\", \"Did not connect interface to channel gating\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected the translocation machinery to human disease by showing SEC63 loss-of-function mutations cause autosomal dominant polycystic liver disease.\",\n      \"evidence\": \"Human genetic linkage, mutation analysis, and sequencing across families\",\n      \"pmids\": [\"15133510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the molecular pathway from translocation defect to cyst formation\", \"Two-hit cellular mechanism not yet defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined SEC63's substrate-specific role in human cells, distinguishing it from SEC62 and linking its J domain (BiP recruitment) to quantity control of polytopic membrane proteins.\",\n      \"evidence\": \"siRNA knockdown/overexpression, semi-permeabilized and intact-cell transport assays, J-domain mutagenesis, and CK2 phosphorylation site mapping in human cells\",\n      \"pmids\": [\"22375059\", \"23166619\", \"23287549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate selection rules only partially defined\", \"Functional consequence of CK2 phosphorylation beyond enhanced SEC62 binding unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established that the Sec62-Sec63 translocon functions in membrane protein topogenesis, not just soluble protein import, and that the Sec63 N-terminus stabilizes the assembled SEC complex.\",\n      \"evidence\": \"Yeast mutagenesis, N-terminal deletion, co-IP, Blue-Native PAGE, and metabolic-labeling translocation assays\",\n      \"pmids\": [\"25097231\", \"31195072\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic coupling of complex stability to topogenesis not structurally resolved\", \"Findings derived from yeast\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed that SEC63 loss is buffered by selective IRE1\\u03b1-XBP1 UPR activation required for PC1 GPS cleavage, defining the protective pathway underlying the disease mechanism.\",\n      \"evidence\": \"Conditional knockout mice, co-IP of the SEC63-PC1 complex, XBP1 epistasis, and PC1 GPS cleavage rescue assays\",\n      \"pmids\": [\"25844898\", \"30745418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SEC63 loss is sensed to activate IRE1\\u03b1 not defined\", \"Direct biochemical role of SEC63 in PC1 maturation unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the biophysical signal-peptide features that route substrates to the SEC62/SEC63/BiP-dependent import pathway, explaining its substrate selectivity.\",\n      \"evidence\": \"Unbiased proteomics with siRNA knockdown in intact cells, in vitro translocation, and signal-peptide mutagenesis\",\n      \"pmids\": [\"32133789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of each signal-peptide feature not fully separated\", \"BiP requirement defined for a substrate subset only\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the structural mechanism of channel activation, showing Sec63 partially opens the Sec61 lateral gate via three contact regions and licenses Sec62 to displace the plug and open the pore.\",\n      \"evidence\": \"Cryo-EM of Sec61-Sec62-Sec63 complexes from two species, molecular dynamics simulations, co-precipitation, and interface mutagenesis\",\n      \"pmids\": [\"33398175\", \"33780447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Captured states do not include an engaged translocating substrate\", \"Conformational role of post-translational modifications in gating not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed SEC63 downstream of SOX9 transcriptional control and linked its expression to primary cilium maintenance in biliary epithelium.\",\n      \"evidence\": \"ChIP, luciferase reporter assays, siRNA knockdown, and SEC63 overexpression rescue\",\n      \"pmids\": [\"33512716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking SEC63 levels to ciliogenesis unresolved\", \"Single-lineage cell context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended SEC63 function beyond the ER, showing IRE1\\u03b1 phosphorylation activates a SEC63-ACLY axis driving acetyl-CoA/lipid metabolism, nuclear UPR target induction, and HCC metastasis.\",\n      \"evidence\": \"GST pull-down, co-IP/mass spectrometry, phosphorylation and ubiquitination assays, RNA-seq, metabolite detection, and migration/invasion assays\",\n      \"pmids\": [\"37122003\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear translocation mechanism of an ER membrane protein not defined\", \"Generality beyond HCC unestablished\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified palmitoylation as a lipid-responsive modification of SEC63 that promotes ER stress, linking metabolic input to SEC63-dependent stress signaling.\",\n      \"evidence\": \"Palmitoylation proteomics, C490 site-directed mutagenesis, and Western blot for ER stress markers in ovarian granulosa cells\",\n      \"pmids\": [\"41845436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzyme catalyzing SEC63 palmitoylation not identified\", \"Mechanistic link between palmitoylation and downstream stress effectors undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SEC63's diverse post-translational modifications (CK2, IRE1\\u03b1, palmitoylation) and non-ER (nuclear) functions integrate with its translocation cochaperone role to control proteostasis and disease remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coupling channel gating to modification state\", \"Substrate-level basis of PCLD pathogenesis not fully reconstituted\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 4, 20]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 6, 13]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [6, 11, 13]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [10, 16, 21]}\n    ],\n    \"complexes\": [\n      \"Sec61-Sec62-Sec63 translocon complex\",\n      \"SEC63-polycystin-1 (PC1) complex\"\n    ],\n    \"partners\": [\n      \"SEC61\",\n      \"SEC62\",\n      \"BiP/Kar2p\",\n      \"SEC66/HSS1\",\n      \"polycystin-1 (PC1)\",\n      \"CK2\",\n      \"IRE1\\u03b1\",\n      \"ACLY\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}