Affinage

SEC63

Translocation protein SEC63 homolog · UniProt Q9UGP8

Length
760 aa
Mass
88.0 kDa
Annotated
2026-06-10
37 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1993 High

    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

    PMID:8305736

    Open questions at the time
    • Genetic interaction did not resolve which translocation step BiP recruitment drives
    • No direct biochemical reconstitution of the Sec63 J-domain/BiP cycle
  2. 1993 Medium

    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

    PMID:8257794 PMID:8514125

    Open questions at the time
    • Mechanistic basis of the SON1/nuclear-localization connection unresolved
    • Stoichiometry of Sec66 within the complex not defined
  3. 2000 Medium

    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

    PMID:10799540

    Open questions at the time
    • Did not define substrate selectivity of the mammalian complex
    • Subunit stoichiometry and architecture unresolved
  4. 2003 Medium

    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

    PMID:12518317

    Open questions at the time
    • Interaction mapped in yeast, not validated for human orthologs at the time
    • Did not connect interface to channel gating
  5. 2004 High

    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

    PMID:15133510

    Open questions at the time
    • Did not establish the molecular pathway from translocation defect to cyst formation
    • Two-hit cellular mechanism not yet defined
  6. 2012 Medium

    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

    PMID:22375059 PMID:23166619 PMID:23287549

    Open questions at the time
    • Substrate selection rules only partially defined
    • Functional consequence of CK2 phosphorylation beyond enhanced SEC62 binding unclear
  7. 2014 Medium

    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

    PMID:25097231 PMID:31195072

    Open questions at the time
    • Mechanistic coupling of complex stability to topogenesis not structurally resolved
    • Findings derived from yeast
  8. 2015 High

    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

    PMID:25844898 PMID:30745418

    Open questions at the time
    • How SEC63 loss is sensed to activate IRE1α not defined
    • Direct biochemical role of SEC63 in PC1 maturation unresolved
  9. 2020 High

    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

    PMID:32133789

    Open questions at the time
    • Quantitative contribution of each signal-peptide feature not fully separated
    • BiP requirement defined for a substrate subset only
  10. 2021 High

    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

    PMID:33398175 PMID:33780447

    Open questions at the time
    • Captured states do not include an engaged translocating substrate
    • Conformational role of post-translational modifications in gating not addressed
  11. 2021 Medium

    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

    PMID:33512716

    Open questions at the time
    • Mechanism linking SEC63 levels to ciliogenesis unresolved
    • Single-lineage cell context
  12. 2023 Medium

    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

    PMID:37122003

    Open questions at the time
    • Nuclear translocation mechanism of an ER membrane protein not defined
    • Generality beyond HCC unestablished
  13. 2026 Medium

    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

    PMID:41845436

    Open questions at the time
    • Enzyme catalyzing SEC63 palmitoylation not identified
    • Mechanistic link between palmitoylation and downstream stress effectors undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No unified model coupling channel gating to modification state
  • Substrate-level basis of PCLD pathogenesis not fully reconstituted

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 2 GO:0060090 molecular adaptor activity 2 GO:0042393 histone binding 1
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005634 nucleus 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-9609507 Protein localization 3
Partners
ACLYBIP/KAR2PCK2IRE1ΑPOLYCYSTIN-1 (PC1)SEC61SEC62SEC66/HSS1
Complex memberships
SEC63-polycystin-1 (PC1) complexSec61-Sec62-Sec63 translocon complex

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 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. Biochemical fractionation, primary sequence analysis, co-immunoprecipitation The Journal of biological chemistry Medium 10799540
1993 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. Yeast genetic epistasis, synthetic lethality, allele-specific suppression, Northern blot Molecular biology of the cell High 8305736
1993 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. Extragenic suppressor screen, genetic complementation, gene mapping Genetics Medium 8514125
1993 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. High-copy suppressor cloning, gene disruption, pulse-chase translocation assay, synthetic lethality Molecular biology of the cell Medium 8257794
2003 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. Yeast two-hybrid, pull-down assays, domain mapping Yeast (Chichester, England) Medium 12518317
2004 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. Human genetic linkage and mutation analysis, sequencing Nature genetics High 15133510
2012 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. siRNA knockdown, semi-permeabilized cell transport assay Journal of cell science Medium 22375059
2012 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. In vitro kinase assay with deletion mutants and peptide library, pull-down assay, co-immunoprecipitation Biochimica et biophysica acta Medium 23287549
2012 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. Overexpression and siRNA knockdown in human cell lines, Western blot, J-domain mutagenesis PloS one Medium 23166619
2011 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. Yeast two-hybrid screen, biochemical interaction characterization FEBS letters Low 21251912
2015 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. Murine genetic models (conditional knockout), co-immunoprecipitation, in vivo XBP1 overexpression rescue, PC1 GPS cleavage assay The Journal of clinical investigation High 25844898
2014 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. Yeast mutagenesis, co-immunoprecipitation, metabolic labeling translocation assay Journal of cell science Medium 25097231
2019 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-terminal deletion mutagenesis in yeast, Blue-Native PAGE, 5-min metabolic labeling translocation assay Biochimica et biophysica acta. General subjects Medium 31195072
2020 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. Unbiased proteomics (in intact human cells with siRNA knockdown), in vitro translocation assay, signal peptide mutagenesis The FEBS journal High 32133789
2021 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. Cryo-electron microscopy structure determination, molecular dynamics simulations, mutagenesis of Sec61-Sec63 contact interfaces Nature structural & molecular biology High 33398175
2021 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. Molecular dynamics simulations, co-precipitation assay, molecular docking PLoS computational biology Medium 33780447
2019 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. Conditional knockout mouse genetics, in vivo XBP1s rescue, kidney function assays, histology Journal of the American Society of Nephrology High 30745418
2021 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. Chromatin immunoprecipitation (ChIP), luciferase reporter assay, siRNA knockdown, SEC63 overexpression rescue The Journal of pathology Medium 33512716
2023 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. GST pull-down, co-immunoprecipitation/mass spectrometry, in vivo ubiquitination/phosphorylation assay, RNA-sequencing, metabolites detection, immunofluorescence, transwell migration/invasion assays Journal of experimental & clinical cancer research Medium 37122003
2010 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. Split-ubiquitin membrane yeast two-hybrid, genetic epistasis, vacuolar acidification assay, Western blot for Vph1 stability Eukaryotic cell Medium 21097665
2012 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. Zebrafish genetic mutant characterization, immunofluorescence, electron microscopy, in situ hybridization for ER stress markers Disease models & mechanisms Medium 22864019
2026 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. Palmitoylation-modified proteomics, site-directed mutagenesis (C490), Western blot for ER stress markers Journal of ovarian research Medium 41845436

Source papers

Stage 0 corpus · 37 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Mutations in SEC63 cause autosomal dominant polycystic liver disease. Nature genetics 196 15133510
2000 Mammalian Sec61 is associated with Sec62 and Sec63. The Journal of biological chemistry 158 10799540
2017 Let's talk about Secs: Sec61, Sec62 and Sec63 in signal transduction, oncology and personalized medicine. Signal transduction and targeted therapy 140 29263911
2012 Different effects of Sec61α, Sec62 and Sec63 depletion on transport of polypeptides into the endoplasmic reticulum of mammalian cells. Journal of cell science 134 22375059
1993 Genetic interactions between KAR2 and SEC63, encoding eukaryotic homologues of DnaK and DnaJ in the endoplasmic reticulum. Molecular biology of the cell 125 8305736
1993 Extragenic suppressors of mutations in the cytoplasmic C terminus of SEC63 define five genes in Saccharomyces cerevisiae. Genetics 54 8514125
2023 Activation of ACLY by SEC63 deploys metabolic reprogramming to facilitate hepatocellular carcinoma metastasis upon endoplasmic reticulum stress. Journal of experimental & clinical cancer research : CR 52 37122003
2015 Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity. The Journal of clinical investigation 52 25844898
2021 Stepwise gating of the Sec61 protein-conducting channel by Sec63 and Sec62. Nature structural & molecular biology 49 33398175
2020 Identification of signal peptide features for substrate specificity in human Sec62/Sec63-dependent ER protein import. The FEBS journal 46 32133789
2006 Extensive mutational analysis of PRKCSH and SEC63 broadens the spectrum of polycystic liver disease. Human mutation 46 16835903
1993 Suppression of a sec63 mutation identifies a novel component of the yeast endoplasmic reticulum translocation apparatus. Molecular biology of the cell 43 8257794
2010 Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63. Clinical genetics 33 20095989
2003 Identification of novel protein-protein interactions at the cytosolic surface of the Sec63 complex in the yeast ER membrane. Yeast (Chichester, England) 30 12518317
2014 The Sec62-Sec63 translocon facilitates translocation of the C-terminus of membrane proteins. Journal of cell science 29 25097231
2021 Emerging View on the Molecular Functions of Sec62 and Sec63 in Protein Translocation. International journal of molecular sciences 27 34884562
2012 Loss of heterozygosity is present in SEC63 germline carriers with polycystic liver disease. PloS one 25 23209713
2013 Hepatocellular carcinoma as extracolonic manifestation of Lynch syndrome indicates SEC63 as potential target gene in hepatocarcinogenesis. Scandinavian journal of gastroenterology 22 23537056
2012 Mutation of sec63 in zebrafish causes defects in myelinated axons and liver pathology. Disease models & mechanisms 21 22864019
2012 CK2 phosphorylation of human Sec63 regulates its interaction with Sec62. Biochimica et biophysica acta 20 23287549
2019 Spliced XBP1 Rescues Renal Interstitial Inflammation Due to Loss of Sec63 in Collecting Ducts. Journal of the American Society of Nephrology : JASN 19 30745418
2011 An interaction between human Sec63 and nucleoredoxin may provide the missing link between the SEC63 gene and polycystic liver disease. FEBS letters 19 21251912
2012 Role of human sec63 in modulating the steady-state levels of multi-spanning membrane proteins. PloS one 15 23166619
2010 Hph1 and Hph2 are novel components of the Sec63/Sec62 posttranslational translocation complex that aid in vacuolar proton ATPase biogenesis. Eukaryotic cell 15 21097665
2021 How does Sec63 affect the conformation of Sec61 in yeast? PLoS computational biology 12 33780447
2014 Brr2p carboxy-terminal Sec63 domain modulates Prp16 splicing RNA helicase. Nucleic acids research 12 25428373
2021 SEC62 and SEC63 Expression in Hepatocellular Carcinoma and Tumor-Surrounding Liver Tissue. Visceral medicine 11 33977099
2021 Deletion of Sox9 in the liver leads to hepatic cystogenesis in mice by transcriptionally downregulating Sec63. The Journal of pathology 10 33512716
2019 Proper insertion and topogenesis of membrane proteins in the ER depend on Sec63. Biochimica et biophysica acta. General subjects 10 31195072
2019 microRNA-1 Regulates NCC Migration and Differentiation by Targeting sec63. International journal of biological sciences 10 31754327
2024 LncRNA WFDC21P interacts with SEC63 to promote gastric cancer malignant behaviors by regulating calcium homeostasis signaling pathway. Cancer cell international 3 38528582
2009 The uterine expression of SEC63 gene is up-regulated at implantation sites in association with the decidualization during the early pregnancy in mice. Reproductive biology and endocrinology : RB&E 3 19208265
2018 FBP21's C-Terminal Domain Remains Dynamic When Wrapped around the c-Sec63 Unit of Brr2 Helicase. Biophysical journal 2 30558886
1997 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. Yeast (Chichester, England) 1 9153759
2026 Role and mechanism of palmitic acid-regulated palmitoylation modification of SEC63 protein during endoplasmic reticulum stress in human ovarian granulosa tumor cells (KGN). Journal of ovarian research 0 41845436
2026 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. Cureus 0 41994676
2025 Sec61s and Sec62/Sec63 Genes Are Essential for Survival by Regulating the Gut and Cuticle Development in Locusta migratoria. Insects 0 40558980

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