SEC63 (also DNAJC23) is a multi-pass endoplasmic reticulum membrane protein and an auxiliary component of the Sec61 translocon. It contains a luminal J-domain (DnaJ/Hsp40-type) and two Sec63 domains. Together with SEC62 it forms the SEC62-SEC63 subcomplex that supports cotranslational and post-translational translocation of precursor polypeptides into the ER. Its defining mechanism is co-chaperone activity, in which the luminal J-domain recruits and stimulates the ATPase cycle of the ER Hsp70 chaperone BiP (HSPA5), positioning BiP on incoming polypeptides at the translocon to drive and gate their translocation into the ER lumen. SEC63 cooperates with SEC62 and BiP in importing small presecretory proteins with short, apolar signal peptides, and is required for efficient biogenesis and trafficking of polycystin-1 (PKD1). SEC63 is widely expressed with high levels in liver, and loss-of-function variants cause autosomal dominant polycystic liver disease (PCLD2).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003723 RNA binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: RNA binding is not an established core function of SEC63, an ER-membrane translocon J-domain co-chaperone. This phylogenetic (IBA) annotation appears propagated from high-throughput mRNA-interactome captures rather than a demonstrated, conserved sequence-specific RNA-binding activity; the J-domain and Sec63 domains are not canonical RNA-binding modules. Reason: RNA binding is not a demonstrated core function of SEC63; the IBA propagation likely derives from incidental mRNA-interactome captures (consistent with translocon proximity to translating ribosomes/mRNA) rather than a sequence-specific RNA-binding activity, so it is retained but marked non-core. Supporting Evidence: file:human/SEC63/SEC63-uniprot.txt Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER) |
| GO:0006614 SRP-dependent cotranslational protein targeting to membrane | IBA GO_REF:0000033 | ACCEPT | Summary: SEC63 participates in cotranslational translocation of precursors into the ER as a translocon-associated co-chaperone, consistent with the conserved family role. Reason: Core biological process; SEC63 supports cotranslational transport of precursor polypeptides across the ER membrane. Supporting Evidence: file:human/SEC63/SEC63-uniprot.txt Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER) |
| GO:0006620 post-translational protein targeting to endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: SEC63 mediates post-translational targeting/translocation of precursors to the ER membrane; conserved across the family. Reason: Core biological process; SEC63 (with SEC62 and BiP) supports post-translational ER import. Supporting Evidence: file:human/SEC63/SEC63-uniprot.txt Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER) |
| GO:0031207 Sec62/Sec63 complex | IBA GO_REF:0000033 | ACCEPT | Summary: SEC63 is a defining subunit of the SEC62-SEC63 subcomplex of the ER translocon, conserved across the family. Reason: Core cellular component; SEC63 forms the Sec62/Sec63 complex with SEC62. Supporting Evidence: file:human/SEC63/SEC63-uniprot.txt different auxiliary components such as SEC62 and SEC63 |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: SEC63 is a multi-pass ER membrane protein; ER membrane is its core localization. Reason: Core cellular component; UniProt records SEC63 as an ER-membrane multi-pass protein. Supporting Evidence: file:human/SEC63/SEC63-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Multi-pass |
| GO:0006614 SRP-dependent cotranslational protein targeting to membrane | IEA GO_REF:0000117 | ACCEPT | Summary: Electronic assignment of cotranslational ER targeting, consistent with the IBA/IMP evidence. Reason: Correct core biological process; redundant with experimental and phylogenetic evidence. Supporting Evidence: file:human/SEC63/SEC63-uniprot.txt Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER) |
| GO:0006620 post-translational protein targeting to endoplasmic reticulum membrane | IEA GO_REF:0000117 | ACCEPT | Summary: Electronic assignment of post-translational ER targeting, consistent with IBA/IMP evidence. Reason: Correct core biological process; redundant with experimental evidence. Supporting Evidence: file:human/SEC63/SEC63-uniprot.txt Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER) |
| GO:0005515 protein binding | IPI PMID:21251912 An interaction between human Sec63 and nucleoredoxin may pro... | KEEP AS NON CORE | Summary: SEC63 interacts with cytosolic nucleoredoxin (NRX), an interaction proposed to link SEC63 to Wnt signaling and to polycystic liver disease. A genuine and disease-relevant interaction, but bare protein binding is uninformative. Reason: Records the real SEC63-nucleoredoxin interaction (disease-relevant) but bare protein binding is uninformative and not the core translocon co-chaperone function. Supporting Evidence: PMID:21251912 we identified the cytosolic protein nucleoredoxin (NRX) as an interaction partner of human Sec63 |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | KEEP AS NON CORE | Summary: Alternative-splicing interactome screen capture; bare protein binding is uninformative. Reason: High-throughput interactome interaction; uninformative bare term not elevated to core. Supporting Evidence: file:human/SEC63/SEC63-uniprot.txt Q9UGP8; Q6FHY5: MEOX2 |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) evidence for ER localization, consistent with SEC63's translocon-associated function. Reason: Correct compartment; the more specific ER membrane localization is also annotated. Supporting Evidence: file:human/SEC63/SEC63-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0031204 post-translational protein targeting to membrane, translocation | IMP PMID:29719251 Chaperone-Mediated Sec61 Channel Gating during ER Import of ... | ACCEPT | Summary: SEC63, with BiP, acts as an auxiliary translocation component during chaperone-mediated Sec61 channel gating for import of small precursors; the J-domain (H132/HPD) mutant reduces translocation. Reason: Core biological process with direct experimental (IMP) support; SEC63 supports translocation of precursors across the ER membrane. Supporting Evidence: PMID:29719251 Sec63 and the lumenal chaperone BiP act as auxiliary translocation components |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | KEEP AS NON CORE | Summary: SEC63 was captured in a high-throughput mRNA-interactome (RNA-binding proteome) screen. This is real data but does not establish a physiological RNA-binding function for an ER-membrane translocon co-chaperone. Reason: High-throughput proteome-wide RNA-interactome capture; not a demonstrated core function of SEC63 and likely reflects proximity to translating ribosomes/mRNA at the translocon rather than direct sequence-specific RNA binding. Supporting Evidence: file:human/SEC63/SEC63-uniprot.txt F:RNA binding; HDA:UniProtKB |
| GO:0006614 SRP-dependent cotranslational protein targeting to membrane | IMP PMID:22375059 Different effects of Sec61Ξ±, Sec62 and Sec63 depletion on tr... | ACCEPT | Summary: Depletion studies of Sec61/Sec62/Sec63 demonstrate SEC63's role in cotranslational transport of polypeptides into the ER. Reason: Core biological process with experimental (IMP) support. Supporting Evidence: file:human/SEC63/SEC63-uniprot.txt Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER) |
| GO:0006620 post-translational protein targeting to endoplasmic reticulum membrane | IMP PMID:22375059 Different effects of Sec61Ξ±, Sec62 and Sec63 depletion on tr... | ACCEPT | Summary: Depletion studies demonstrate SEC63's role in post-translational targeting of precursors to the ER membrane. Reason: Core biological process with experimental (IMP) support. Supporting Evidence: file:human/SEC63/SEC63-uniprot.txt Mediates cotranslational and post-translational transport of certain precursor polypeptides across endoplasmic reticulum (ER) |
| GO:0016020 membrane | IDA PMID:22375059 Different effects of Sec61Ξ±, Sec62 and Sec63 depletion on tr... | KEEP AS NON CORE | Summary: SEC63 is a membrane protein; "membrane" is a correct but generic parent of the specific ER membrane localization. Reason: Correct but generic; ER membrane (GO:0005789) is the more specific and informative localization. Supporting Evidence: file:human/SEC63/SEC63-uniprot.txt Multi-pass |
| GO:0005783 endoplasmic reticulum | TAS PMID:10799540 Mammalian Sec61 is associated with Sec62 and Sec63. | ACCEPT | Summary: SEC63 is an ER protein associated with the Sec61 translocon; ER localization is correct. Reason: Correct compartment; redundant with the more specific ER membrane annotations. Supporting Evidence: PMID:10799540 a membrane protein complex that consists of the Sec61p complex and the Sec62p-Sec63p subcomplex |
| GO:0006612 protein targeting to membrane | TAS PMID:10799540 Mammalian Sec61 is associated with Sec62 and Sec63. | ACCEPT | Summary: SEC63 is involved in targeting/translocation of proteins to the ER membrane; protein targeting to membrane is a correct but generic parent of the specific ER translocation terms. Reason: Correct general biological process; the specific post-translational/cotranslational ER targeting terms better capture SEC63's role. Supporting Evidence: PMID:10799540 a membrane protein complex that consists of the Sec61p |
| GO:0038023 signaling receptor activity | TAS PMID:10799540 Mammalian Sec61 is associated with Sec62 and Sec63. | MARK AS OVER ANNOTATED | Summary: SEC63 is a translocon-associated J-domain co-chaperone that recruits/stimulates BiP, not a signal-transduction (signaling) receptor. The signaling receptor activity term mischaracterizes its molecular function; this is a legacy ProtInc annotation. Reason: SEC63 functions as a DnaJ-type co-chaperone at the Sec61 translocon, not a signal-transduction receptor; signaling receptor activity over-extends/misframes its molecular function. Supporting Evidence: file:human/SEC63/SEC63-uniprot.txt a membrane protein complex that consists of the Sec61p complex and the Sec62p-Sec63p subcomplex |
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Download this section (compressed HTML)Q: Should SEC63 carry an explicit Hsp70/BiP co-chaperone or heat-shock-protein-binding molecular-function annotation to capture its J-domain stimulation of BiP ATPase, which the current GOA does not represent?
Q: How does the SEC63-nucleoredoxin (Wnt-pathway) interaction mechanistically connect translocon function to the cystogenesis seen in PCLD2?
Experiment: Reconstitute BiP ATPase stimulation by wild-type versus HPD-mutant (H132Q) SEC63 J-domain and correlate with translocation efficiency of defined precursors to establish the J-domain/BiP molecular function.
Experiment: Express PCLD2 truncating SEC63 variants and quantify polycystin-1 (PKD1) biogenesis/trafficking and BiP recruitment at the translocon to link the molecular defect to disease.
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