SERPINH1 (Serpin H1, better known as HSP47, also called colligin / gp46) is an endoplasmic reticulum-resident, collagen-specific molecular chaperone. Although it belongs to the serpin superfamily by fold, it is non-inhibitory and does not act as a protease inhibitor. In the ER lumen HSP47 binds specifically to the folded triple-helical region of procollagen, stabilizing the nascent triple helix, preventing local unfolding and premature aggregation, and serving as a quality-control factor in collagen biosynthesis. HSP47 accompanies procollagen from the ER to the ER-Golgi intermediate compartment/cis-Golgi, where the lower pH triggers its release; it then recycles back to the ER through its C-terminal RDEL retrieval signal. It is heat-shock inducible. Loss-of-function variants cause autosomal-recessive osteogenesis imperfecta type X (OI10), underscoring its essential role in collagen maturation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004867 serine-type endopeptidase inhibitor activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Phylogenetic transfer of serpin protease-inhibitor activity. HSP47 is a well-documented non-inhibitory serpin that functions as a collagen chaperone, not a protease inhibitor. Reason: Inferred from the serpin fold/family, but HSP47/SERPINH1 lacks functional protease-inhibitory activity; its characterized role is collagen binding/chaperoning. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt Binds specifically to collagen. Could be involved as a chaperone in the biosynthetic pathway of collagen. |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: HSP47 acts in the endoplasmic reticulum, where it chaperones procollagen. ER localization is well established. Reason: Consistent with UniProt subcellular location (ER lumen) and multiple experimental annotations; the ER is the genuine site of HSP47 action. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0030199 collagen fibril organization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: HSP47 contributes to collagen biogenesis; proper fibril organization downstream depends on correctly matured procollagen. HSP47 itself acts in the ER, upstream of extracellular fibril assembly. Reason: Collagen fibril organization is a downstream/extracellular consequence of HSP47's ER chaperone activity; a reasonable process annotation but not its direct molecular role. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt Binds specifically to collagen. Could be involved as a chaperone in the biosynthetic pathway of collagen. |
| GO:0004867 serine-type endopeptidase inhibitor activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro serpin-family transfer of protease-inhibitor activity. HSP47 is non-inhibitory. Reason: Domain-based transfer; HSP47/SERPINH1 does not function as a serine protease inhibitor despite its serpin fold. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt Binds specifically to collagen. Could be involved as a chaperone in the biosynthetic pathway of collagen. |
| GO:0005518 collagen binding | IEA GO_REF:0000002 | ACCEPT | Summary: HSP47 binds specifically to collagen (folded triple helix); this is its defining, core molecular function. Reason: Directly supported by UniProt FUNCTION and by extensive literature; collagen binding is the central molecular activity of HSP47. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt Binds specifically to collagen. |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000044 | ACCEPT | Summary: Automated (UniProt SubCell) annotation of ER lumen, the precise compartment where HSP47 chaperones procollagen. Reason: Matches UniProt subcellular location exactly; ER lumen is the genuine and specific HSP47 compartment. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0006457 protein folding | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Process annotation inferred from the protein folding chaperone MF. HSP47 stabilizes already-folded triple-helical procollagen and prevents aggregation rather than catalyzing folding de novo. Reason: HSP47 is a holdase-type collagen chaperone, not a foldase; protein folding is a reasonable downstream process but non-core relative to collagen binding. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt Could be involved as a chaperone in the biosynthetic pathway of collagen. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Large-scale neurodegeneration interactome screen capturing many HSP47 interactions with diverse partners (e.g. CDH1, ETS2), none of which are collagen. Bare protein binding is uninformative and does not reflect HSP47's collagen-specific function. Reason: High-throughput interactome partners unrelated to HSP47's characterized collagen-chaperone role; uninformative protein binding term. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt Binds specifically to collagen. |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl ortholog-based cytoplasm annotation. HSP47 is an ER-lumenal protein; the cytoplasm term is a coarse parent localization inconsistent with its specific ER-lumen residence. Reason: Conflicts with the well-established ER-lumen localization; cytoplasm is an over-general/ortholog-transfer localization for this secretory-pathway protein. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl ortholog-based ER localization, consistent with HSP47's documented ER residence. Reason: Agrees with UniProt and experimental ER annotations; the genuine compartment of HSP47. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0044183 protein folding chaperone | IEA GO_REF:0000107 | ACCEPT | Summary: HSP47 is a collagen-specific molecular chaperone; the generic chaperone MF is correct but the precise, informative MF is collagen binding. Reason: HSP47 functions as a molecular chaperone for procollagen; supported by UniProt FUNCTION. Captured more specifically by collagen binding in core_functions. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt Could be involved as a chaperone in the biosynthetic pathway of collagen. |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) evidence for ER localization, consistent with HSP47's role as an ER collagen chaperone. Reason: IDA-supported ER localization corroborating UniProt; genuine HSP47 compartment. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0031012 extracellular matrix | HDA PMID:28327460 Comprehensive proteomic characterization of stem cell-derive... | KEEP AS NON CORE | Summary: High-throughput matrisome/ECM proteomics detection. HSP47 is ER-resident; ECM detection likely reflects co-secretion with collagen or proteomic carryover, not a core localization. Reason: HDA ECM detection is peripheral to HSP47's documented ER-lumen site of action. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0031012 extracellular matrix | HDA PMID:28675934 Characterization of the Extracellular Matrix of Normal and D... | KEEP AS NON CORE | Summary: High-throughput ECM proteomics detection of HSP47, peripheral to its ER chaperone role. Reason: HDA matrisome detection; not the core ER-lumen localization of HSP47. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0031012 extracellular matrix | HDA PMID:25037231 Extracellular matrix signatures of human primary metastatic ... | KEEP AS NON CORE | Summary: High-throughput ECM proteomics detection of HSP47, peripheral to its ER chaperone role. Reason: HDA matrisome detection; not the core ER-lumen localization of HSP47. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0045121 membrane raft | IDA PMID:25204797 Flotillin-1 facilitates toll-like receptor 3 signaling in hu... | KEEP AS NON CORE | Summary: Reported cell-surface/membrane-raft pool of HSP47 in a specific context. A minor, non-canonical localization relative to its predominant ER-lumen residence. Reason: A specialized, context-dependent localization; peripheral to HSP47's core ER collagen-chaperone function. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | MARK AS OVER ANNOTATED | Summary: mRNA-interactome-capture detection of HSP47 as an RNA-binder. There is no characterized RNA-dependent function for HSP47; this is a generic proteome-wide capture result. Reason: High-throughput RNA-interactome capture without a validated functional role; not part of HSP47's collagen-chaperone function. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt Binds specifically to collagen. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-2022073 | ACCEPT | Summary: Curated (Reactome) ER lumen localization, matching the precise compartment of HSP47. Reason: Consistent with UniProt ER-lumen location; the genuine and specific HSP47 compartment. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-2089971 | ACCEPT | Summary: Curated (Reactome) ER lumen localization, matching the precise compartment of HSP47. Reason: Consistent with UniProt ER-lumen location; the genuine and specific HSP47 compartment. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0004867 serine-type endopeptidase inhibitor activity | TAS PMID:1309665 Cloning of a human collagen-binding protein, and its homolog... | MARK AS OVER ANNOTATED | Summary: Author-stated serpin-family inhibitor classification. HSP47 is a non-inhibitory serpin; the inhibitory activity is a historical fold-based attribution. Reason: HSP47/SERPINH1 does not function as a protease inhibitor despite the serpin fold; its characterized function is collagen chaperoning. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt Binds specifically to collagen. |
| GO:0005518 collagen binding | NAS PMID:1309665 Cloning of a human collagen-binding protein, and its homolog... | ACCEPT | Summary: Author-stated collagen binding, HSP47's defining molecular function. Reason: Collagen binding is the core, well-established molecular activity of HSP47; supported by UniProt and literature. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt Binds specifically to collagen. |
| GO:0005783 endoplasmic reticulum | TAS PMID:1309665 Cloning of a human collagen-binding protein, and its homolog... | ACCEPT | Summary: Author-stated ER localization, consistent with HSP47's documented ER residence. Reason: Agrees with UniProt and experimental evidence; genuine HSP47 compartment. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0005783 endoplasmic reticulum | TAS PMID:7656593 Isolation, characterization and chromosomal assignment of hu... | ACCEPT | Summary: Author-stated ER localization, consistent with HSP47's documented ER residence. Reason: Agrees with UniProt and experimental evidence; genuine HSP47 compartment. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0006986 response to unfolded protein | TAS PMID:1309665 Cloning of a human collagen-binding protein, and its homolog... | KEEP AS NON CORE | Summary: HSP47 is heat-shock inducible, historically framed as a stress/UPR-associated chaperone. However it is collagen-specific and not a general unfolded-protein-response chaperone. Reason: HSP47 is stress-inducible but its substrate specificity is collagen, not general unfolded proteins; this process annotation is peripheral to its core role. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt INDUCTION: By heat shock. |
| GO:0005793 endoplasmic reticulum-Golgi intermediate compartment | IDA PMID:15308636 Proteomics of endoplasmic reticulum-Golgi intermediate compa... | ACCEPT | Summary: Direct evidence that HSP47 localizes to the ER-Golgi intermediate compartment, consistent with its pH-dependent procollagen escort and recycling itinerary. Reason: IDA-supported ERGIC localization matching the established HSP47 trafficking cycle (procollagen escort to ERGIC/cis-Golgi, pH-triggered release, RDEL-mediated return). Supporting Evidence: file:human/SERPINH1/SERPINH1-goa.tsv GO:0005793 endoplasmic reticulum-Golgi intermediate compartment |
| GO:0005518 collagen binding | NAS PMID:7656593 Isolation, characterization and chromosomal assignment of hu... | ACCEPT | Summary: Author-stated collagen binding, HSP47's defining molecular function. Reason: Collagen binding is the core, well-established molecular activity of HSP47. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt Binds specifically to collagen. |
| GO:0005783 endoplasmic reticulum | NAS PMID:7656593 Isolation, characterization and chromosomal assignment of hu... | ACCEPT | Summary: Author-stated ER localization, consistent with HSP47's documented ER residence. Reason: Agrees with UniProt and experimental evidence; genuine HSP47 compartment. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen. |
| GO:0006986 response to unfolded protein | TAS PMID:10023073 The human genome has only one functional hsp47 gene (CBP2) a... | KEEP AS NON CORE | Summary: Heat-shock/stress-associated chaperone framing of HSP47. HSP47 is collagen-specific rather than a general UPR chaperone. Reason: Stress-inducible but collagen-specific; this process annotation is peripheral to HSP47's core collagen-chaperone role. Supporting Evidence: file:human/SERPINH1/SERPINH1-uniprot.txt INDUCTION: By heat shock. |
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Download this section (compressed HTML)Q: What is the precise structural basis and pH threshold for HSP47 release from procollagen in the ERGIC/cis-Golgi, and how is this coupled to its RDEL-mediated ER retrieval?
Q: Beyond fibrillar collagens, which collagen types and other ER clients (if any) does HSP47 chaperone, and how does substrate specificity arise from triple-helix recognition?
Q: How do OI10-causing SERPINH1 variants mechanistically impair collagen maturation (loss of binding, mislocalization, or destabilization)?
Experiment: Quantitative in vitro binding/turbidity assays with purified HSP47 and triple-helical vs unfolded collagen peptides across a pH gradient to map binding affinity and the pH-dependent release transition.
Experiment: Knock-in of OI10 patient variants in osteoblast or fibroblast models followed by collagen secretion, triple-helix stability, and ER-stress assays.
Experiment: Proximity-labeling (BioID/APEX) of HSP47 in the secretory pathway to define its client repertoire and trafficking-machinery partners during collagen transport.
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