Serpinh1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004867 serine-type endopeptidase inhibitor activity	IBA GO_REF:0000033	REMOVE	Summary: HSP47/Serpinh1 is a member of the serpin superfamily by sequence homology and structural classification, so the IBA annotation reflects broad phylogenetic transfer of an ancestral inhibitory-serpin function. However, HSP47 has evolved to function as a collagen-specific chaperone and does not demonstrate serine protease inhibitor activity. The reactive center loop (RCL) of HSP47 is non-canonical and does not function as an inhibitory serpin. OpenScientist traced the IBA to PANTHER node PTN000156127 and classified the annotation as over-propagated because the source tree does not resolve non-inhibitory HSP47-like serpins from inhibitory relatives. Reason: Although HSP47 belongs to the serpin family by sequence and structure, it has lost protease inhibitor activity through evolution and functions as a collagen-specific chaperone. The IBA inference from the broader serpin family is incorrect for this particular member, which has neofunctionalized. OpenScientist found no experimental IDA/IMP/IPI support for serine protease inhibitor activity in HSP47 and identified the source as an overly broad PANTHER serpin-family transfer. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE PSEUDO OR SUBACTIVITY LOSS Sources checked: PANTHER:PTN000156127 · PANTHER serpin-family source node SUPPORTS SOURCE BUT NOT TARGET The PAINT source node includes inhibitory serpins that support GO:0004867 in the family, but Serpinh1/HSP47 is a non-inhibitory serpin repurposed as an ER collagen-specific chaperone. Supporting Evidence: PMID:27838364 belongs to the serpin family and has the serpin fold; however, it has no serine protease inhibitory activity PMID:21683254 although it does not have serine protease inhibitory activity PMID:12685865 this protein does not appear to inhibit serine proteinases file:mouse/Serpinh1/Serpinh1-hypotheses/function-hypothesis-go-0004867/openscientist.md The current GO:0004867 (serine-type endopeptidase inhibitor activity) annotation for mouse Serpinh1 should be removed. file:mouse/Serpinh1/Serpinh1-deep-research-falcon.md SERPINH1 encodes HSP47, an ER-resident, collagen-specific molecular chaperone that adopts a serpin fold but lacks serine protease inhibitory activity.
GO:0005783 endoplasmic reticulum	IBA GO_REF:0000033	ACCEPT	Summary: HSP47 is well established as an ER-resident protein. It contains a C-terminal RDEL ER retention signal (residues 414-417 per UniProt) and is described by UniProt as localized to the endoplasmic reticulum lumen. Multiple experimental studies confirm ER localization (PMID:10995453, PMID:21606205). The IBA annotation is consistent with all evidence. Reason: ER localization is the primary and best-established subcellular localization for HSP47, consistent with its chaperone function in procollagen maturation. Supported by the C-terminal RDEL retention motif (UniProt FT MOTIF 414..417) and multiple experimental references. Supporting Evidence: PMID:10995453 Hsp47 was shown to transiently bind to newly synthesized procollagen, and to dissociate from procollagen during its transport from the ER to the cis-Golgi compartment PMID:21606205 Mia3 is present in regions demarcated by the ER-resident proteins calnexin and HSP47 file:mouse/Serpinh1/Serpinh1-deep-research-falcon.md The dominant functional localization of SERPINH1/HSP47 is the ER lumen.
GO:0030199 collagen fibril organization	IBA GO_REF:0000033	ACCEPT	Summary: HSP47 plays a critical role in collagen fibril organization through its essential function in ensuring correct triple-helix formation of procollagen. Hsp47 knockout mice show almost no fibrillar structures by silver impregnation analysis and electron microscopy reveals severely reduced collagen fibrils (PMID:10995453). Conditional knockout in chondrocytes causes substantial decrease in type II collagen fibers and misaligned type I collagen molecules (PMID:22492985). The IBA annotation is well supported. Reason: This is a core biological process for HSP47. Without HSP47, collagen cannot form proper triple helices, leading to defective fibril formation. Well supported by both the constitutive knockout (PMID:10995453) and the conditional chondrocyte knockout (PMID:22492985). Supporting Evidence: PMID:10995453 Though fibrillar structures were obviously evident at the periphery of neural tube and in the mesenchymal tissue PMID:22492985 Second-harmonic generation (SHG) analysis and electron microscopy revealed the accumulation of misaligned type I collagen molecules in the intervertebral discs and a substantial decrease in type II collagen fibers file:mouse/Serpinh1/Serpinh1-deep-research-falcon.md HSP47 binds triple-helical procollagen in the ER and stabilizes the triple helix, thereby preventing unfolding and preventing aggregation within the ER lumen
GO:0004867 serine-type endopeptidase inhibitor activity	IEA GO_REF:0000002	REMOVE	Summary: This IEA annotation is based on InterPro serpin domain mappings (IPR000215, IPR033830). While HSP47 contains a serpin domain, it does not function as a serine protease inhibitor. This is a well-known case of a serpin family member that has lost inhibitory function and evolved chaperone activity. Reason: Same rationale as the IBA annotation for GO:0004867. The InterPro-based inference is incorrect because HSP47 has lost protease inhibitor function despite retaining the serpin fold. This is a well-documented case of neofunctionalization within the serpin superfamily. OpenScientist also identified the InterPro IEA as a parallel over-propagation from broad serpin-domain mappings that do not distinguish inhibitory and non-inhibitory family members. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE PSEUDO OR SUBACTIVITY LOSS Sources checked: InterPro:IPR000215 · Serpin family SUPPORTS SOURCE BUT NOT TARGET The family-level InterPro mapping supports inhibitory serpins in general but is too broad for non-inhibitory HSP47/Serpinh1. InterPro:IPR033830 · Serpin H1 serpin domain SUPPORTS SOURCE BUT NOT TARGET The HSP47-specific domain supports the serpin fold, not serine-type endopeptidase inhibitor activity. Supporting Evidence: PMID:27838364 belongs to the serpin family and has the serpin fold; however, it has no serine protease inhibitory activity PMID:21683254 although it does not have serine protease inhibitory activity file:mouse/Serpinh1/Serpinh1-hypotheses/function-hypothesis-go-0004867/openscientist.md An additional IEA annotation exists from InterPro domain IPR000215 (Serpin family), which similarly does not distinguish inhibitory from non-inhibitory members. file:mouse/Serpinh1/Serpinh1-deep-research-falcon.md SERPINH1 encodes HSP47, an ER-resident, collagen-specific molecular chaperone that adopts a serpin fold but lacks serine protease inhibitory activity.
GO:0005518 collagen binding	IEA GO_REF:0000002	ACCEPT	Summary: HSP47 is definitively a collagen-binding protein. This is its primary molecular function -- it specifically and transiently binds to procollagen in the ER. Koide et al. (PMID:10862616) showed that HSP47 preferentially recognizes collagenous Gly-X-Y repeats in triple-helical conformation. The IEA annotation from InterPro domain IPR033830 (Serpin_H1_serpin_dom) is correct. Reason: Collagen binding is the core molecular function of HSP47. It binds specifically to the triple-helical conformation of collagen, as demonstrated experimentally (PMID:10862616). UniProt names this protein 'Collagen-binding protein' as an alternate name. Supporting Evidence: PMID:10862616 our results suggest that HSP47 preferentially recognizes collagenous Gly-X-Y repeats in triple-helical conformation PMID:10995453 Hsp47 is unique in terms of its substrate specificity; that is, it binds exclusively to procollagens and collagens file:mouse/Serpinh1/Serpinh1-deep-research-falcon.md HSP47 binds triple-helical procollagen in the ER and stabilizes the triple helix
GO:0005615 extracellular space	IEA GO_REF:0000002	REMOVE	Summary: This IEA annotation comes from the general InterPro serpin family domain (IPR000215), which maps to extracellular space because many serpins are secreted protease inhibitors. HSP47, however, is an ER-resident protein with a C-terminal RDEL retention signal. It is not normally secreted and does not function in the extracellular space. UniProt subcellular location annotation is 'Endoplasmic reticulum lumen'. Reason: HSP47 is an ER-resident protein with a RDEL retention signal (UniProt FT MOTIF 414..417 'Prevents secretion from ER'). The InterPro-based inference from the general serpin family domain is incorrect for this specific member. Its function is entirely intracellular in the ER lumen.
GO:0005788 endoplasmic reticulum lumen	IEA GO_REF:0000044	ACCEPT	Summary: This annotation is based on UniProt subcellular location mapping. UniProt explicitly states 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'. This is the most precise CC annotation for HSP47 and is well supported by the biology -- HSP47 contains a signal peptide (residues 1-17) for ER targeting and a C-terminal RDEL retention signal. It functions as a soluble chaperone in the ER lumen. Reason: ER lumen is the correct and most specific subcellular localization for HSP47. It is a soluble luminal protein with a signal peptide and RDEL retention motif. This is more precise than the broader 'endoplasmic reticulum' term. Supporting Evidence: file:mouse/Serpinh1/Serpinh1-deep-research-falcon.md The dominant functional localization of SERPINH1/HSP47 is the ER lumen.
GO:0005783 endoplasmic reticulum	ISO GO_REF:0000119	ACCEPT	Summary: ISO transfer from human SERPINH1 (P50454). ER localization is well established for both human and mouse orthologs and is fully consistent with all available evidence. Reason: Redundant with the IBA and IDA annotations for ER, but correctly reflects the biology. The ISO transfer from human is appropriate. Supporting Evidence: file:mouse/Serpinh1/Serpinh1-deep-research-falcon.md The dominant functional localization of SERPINH1/HSP47 is the ER lumen.
GO:0005793 endoplasmic reticulum-Golgi intermediate compartment	ISO GO_REF:0000119	ACCEPT	Summary: ISO transfer from human SERPINH1 (P50454). HSP47 transiently accompanies procollagen from the ER to the cis-Golgi compartment, dissociating in a pH-dependent manner. The ERGIC is along this transport route. While HSP47 is primarily ER-resident, its transient presence in the ERGIC is plausible and consistent with its chaperone escort function. Reason: HSP47 dissociates from procollagen during ER-to-cis-Golgi transport (PMID:10995453), implying transient presence in the ERGIC. This is consistent with the known biology of collagen escort. Supporting Evidence: PMID:10995453 Hsp47 was shown to transiently bind to newly synthesized procollagen, and to dissociate from procollagen during its transport from the ER to the cis-Golgi compartment file:mouse/Serpinh1/Serpinh1-deep-research-falcon.md It transiently accompanies procollagen into early Golgi compartments before dissociation, followed by retrieval to the ER
GO:0045121 membrane raft	ISO GO_REF:0000119	MARK AS OVER ANNOTATED	Summary: ISO transfer from human SERPINH1 (P50454). HSP47 is a soluble ER luminal chaperone; its association with membrane rafts is unexpected and not well supported by primary literature on HSP47 function. This may reflect a co-purification artifact or a non-standard localization that is not central to its function. Reason: HSP47 is a soluble ER luminal chaperone protein. Membrane raft localization is not supported by the core literature on HSP47 function and likely represents an incidental or artifact-based finding from the human ortholog. This does not represent a functionally meaningful localization for this protein.
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000107	ACCEPT	Summary: Automatic transfer from human SERPINH1 via Ensembl Compara. Redundant with multiple other ER annotations but correct. Reason: ER localization is well established. This IEA annotation provides additional orthology-based support consistent with all other evidence. Supporting Evidence: file:mouse/Serpinh1/Serpinh1-deep-research-falcon.md The dominant functional localization of SERPINH1/HSP47 is the ER lumen.
GO:0005793 endoplasmic reticulum-Golgi intermediate compartment	IEA GO_REF:0000107	ACCEPT	Summary: Automatic Ensembl Compara transfer. Redundant with the ISO annotation for the same term. Consistent with the transient ERGIC presence during collagen escort. Reason: Consistent with the known biology of HSP47 escorting procollagen from ER to cis-Golgi. Redundant with the ISO annotation but correctly reflects transient ERGIC localization. Supporting Evidence: file:mouse/Serpinh1/Serpinh1-deep-research-falcon.md It transiently accompanies procollagen into early Golgi compartments before dissociation, followed by retrieval to the ER
GO:0045121 membrane raft	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Automatic Ensembl Compara transfer from human. Same concern as the ISO annotation for membrane raft -- this is unlikely to be a functionally meaningful localization for a soluble ER luminal chaperone. Reason: Same as the ISO annotation review. HSP47 is a soluble ER luminal protein and membrane raft localization is not supported by the core functional literature.
GO:0031012 extracellular matrix	HDA PMID:22159717 The matrisome: in silico definition and in vivo characteriza...	MARK AS OVER ANNOTATED	Summary: This HDA (high-throughput direct assay) annotation comes from a matrisome proteomics study that characterized ECM composition of normal murine tissues. HSP47 was likely detected as a co-purifying protein in the ECM-enriched fraction. While HSP47 is primarily an ER-resident protein, some presence in ECM fractions could reflect incomplete separation or trace extracellular release. HSP47 is not considered an ECM structural component. Reason: HSP47 is an ER-resident chaperone with an RDEL retention signal. Its detection in ECM-enriched fractions from high-throughput proteomics likely reflects co-purification rather than true ECM localization. HSP47 functions intracellularly in the ER lumen and is not a structural ECM component.
GO:0031012 extracellular matrix	HDA PMID:28071719 Quantitative proteomic profiling of the extracellular matrix...	MARK AS OVER ANNOTATED	Summary: Second HDA annotation for ECM localization from another matrisome proteomics study profiling pancreatic islet ECM. Same concern as above; HSP47 is an ER-resident chaperone that co-purifies with collagen-rich ECM fractions. Reason: Same rationale as the other HDA/ECM annotation. HSP47 is not an ECM protein; it is an ER-resident chaperone with RDEL retention signal. Detection in ECM fractions reflects co-purification with its collagen substrates.
GO:0003433 chondrocyte development involved in endochondral bone morphogenesis	IMP PMID:22492985 The molecular chaperone Hsp47 is essential for cartilage and...	KEEP AS NON CORE	Summary: Masago et al. (PMID:22492985) conditionally inactivated Hsp47 in chondrocytes using Col2a1-Cre and showed severe generalized chondrodysplasia, bone deformities, and lower levels of type II and type XI collagen. Conditional null mutant mice died at or shortly after birth. Endochondral bones were severely twisted and shortened with no calcification in sacral vertebral bodies. This demonstrates HSP47 is required for proper chondrocyte development and endochondral bone formation. Reason: While HSP47 is essential for chondrocyte development (as shown by the conditional knockout), this is a downstream consequence of its core molecular function as a collagen chaperone, not a direct biological process function. Collagen is the major structural component of cartilage, so loss of collagen chaperone activity naturally impairs chondrogenesis. This is a pleiotropic effect rather than a core process. Supporting Evidence: PMID:22492985 Hsp47 conditional null mutant mice died just before or shortly after birth, and exhibited severe generalized chondrodysplasia and bone deformities with lower levels of type II and type XI collagen
GO:0030199 collagen fibril organization	IMP PMID:22492985 The molecular chaperone Hsp47 is essential for cartilage and...	ACCEPT	Summary: The conditional chondrocyte knockout showed accumulation of misaligned type I collagen molecules and substantial decrease in type II collagen fibers (PMID:22492985). This directly demonstrates HSP47's role in collagen fibril organization, consistent with the constitutive knockout findings (PMID:10995453). Reason: Collagen fibril organization is a core biological process for HSP47. Both constitutive and conditional knockouts show severe defects in collagen fibril formation. This IMP annotation provides independent tissue-specific confirmation. Supporting Evidence: PMID:22492985 Second-harmonic generation (SHG) analysis and electron microscopy revealed the accumulation of misaligned type I collagen molecules in the intervertebral discs and a substantial decrease in type II collagen fibers file:mouse/Serpinh1/Serpinh1-deep-research-falcon.md HSP47 binds triple-helical procollagen in the ER and stabilizes the triple helix, thereby preventing unfolding and preventing aggregation within the ER lumen
GO:0005783 endoplasmic reticulum	ISO PMID:23269685 Role for phospholipid flippase complex of ATP8A1 and CDC50A ...	ACCEPT	Summary: This ISO annotation references PMID:23269685, a paper about phospholipid flippase complex (ATP8A1/CDC50A) in cell migration. The connection to HSP47 ER localization is unclear from this reference. However, the ER localization itself is well established from multiple other lines of evidence. The ISO annotation was transferred from rat Q9Z1W7. Reason: While the reference PMID:23269685 is not directly relevant to HSP47 function, the ER localization itself is well established and correct. This adds to the multiple concordant ER annotations. Supporting Evidence: file:mouse/Serpinh1/Serpinh1-deep-research-falcon.md The dominant functional localization of SERPINH1/HSP47 is the ER lumen.
GO:0005783 endoplasmic reticulum	IDA PMID:21606205 Global defects in collagen secretion in a Mia3/TANGO1 knocko...	ACCEPT	Summary: Wilson et al. (PMID:21606205) performed immunofluorescent colocalization studies in primary chondrocytes and MEFs. They showed that the Mia3/TANGO1 protein colocalizes with ER-resident proteins calnexin and HSP47 (SerpinH1). This demonstrates direct detection of HSP47 in the ER by immunofluorescence, supporting IDA evidence. Reason: Direct experimental evidence from immunofluorescence demonstrating HSP47 localization in the ER. This is the strongest evidence code among the multiple ER annotations. Supporting Evidence: PMID:21606205 Immunofluorescent colocalization analyses of α-Mia3 SH3 with antibodies against calnexin, Hsp47 (SerpinH1), ERGIC-53 (Lman1), and GM130 in primary chondrocytes reveals an Mia3 protein within punctate structures on the ER membrane file:mouse/Serpinh1/Serpinh1-deep-research-falcon.md The dominant functional localization of SERPINH1/HSP47 is the ER lumen.
GO:0005737 cytoplasm	IDA PMID:8018053 Dynamic variations in the expression of type I collagen and ...	MARK AS OVER ANNOTATED	Summary: Cytoplasm is a broad historical localization call for Hsp47 staining. The biologically precise localization is ER lumen. Reason: Because Serpinh1 is an ER luminal RDEL-retained chaperone, cytoplasm should not be treated as the informative cellular-component annotation. Supporting Evidence: file:mouse/Serpinh1/Serpinh1-notes.md Core evidence: Serpinh1/Hsp47 is an ER-resident, collagen-specific protein folding chaperone file:mouse/Serpinh1/Serpinh1-deep-research-falcon.md The dominant functional localization of SERPINH1/HSP47 is the ER lumen.
GO:0030199 collagen fibril organization	IMP PMID:10995453 Embryonic lethality of molecular chaperone hsp47 knockout mi...	ACCEPT	Summary: Nagai et al. (PMID:10995453) established Hsp47 knockout mice that showed almost no fibrillar structures by silver impregnation, and electron microscopy revealed only a limited number of collagen fibrils in the lamina fibroreticularis and stroma. The mature propeptide-cleaved alpha1(I) chain was hardly detectable. This is the foundational evidence for HSP47's role in collagen fibril organization. Reason: This is the key knockout study demonstrating that HSP47 is essential for collagen fibril formation. The complete absence of mature collagen fibrils in knockout embryos provides definitive IMP evidence. Supporting Evidence: PMID:10995453 silver impregnation analysis was performed. Though fibrillar structures were obviously evident at the periphery of neural tube and in the mesenchymal tissue PMID:10995453 only a limited number of collagen fibrils were observed in the lamina fibroreticularis and stroma file:mouse/Serpinh1/Serpinh1-deep-research-falcon.md HSP47 binds triple-helical procollagen in the ER and stabilizes the triple helix, thereby preventing unfolding and preventing aggregation within the ER lumen
GO:0032964 collagen biosynthetic process	IMP PMID:10995453 Embryonic lethality of molecular chaperone hsp47 knockout mi...	ACCEPT	Summary: The Hsp47 knockout study (PMID:10995453) showed that the mature, propeptide-cleaved alpha1(I) collagen chain was hardly detectable in knockout mice, while immature procollagen and intermediately processed forms accumulated. Procollagen secreted from Hsp47-/- cells showed protease sensitivity indicating aberrant triple helix formation. HSP47 is clearly essential for proper collagen biosynthesis. Reason: HSP47 is required for correct triple-helix formation during collagen biosynthesis. Without it, collagen cannot form rigid triple helices and accumulates in immature forms. This is a core biological process for this protein. Supporting Evidence: PMID:10995453 the mature, propeptide-cleaved α1(I) chain PMID:10995453 This result demonstrated that Hsp47 functions as a molecular chaperone to ensure the rigid triple-helical conformation of type I collagen file:mouse/Serpinh1/Serpinh1-deep-research-falcon.md HSP47 binds triple-helical procollagen in the ER and stabilizes the triple helix, thereby preventing unfolding and preventing aggregation within the ER lumen
GO:0051604 protein maturation	IMP PMID:10995453 Embryonic lethality of molecular chaperone hsp47 knockout mi...	ACCEPT	Summary: Hsp47 knockout mice showed defective processing of procollagen to mature collagen. Immature procollagen and intermediately processed forms accumulated in knockout embryos (PMID:10995453). This demonstrates HSP47's role in protein maturation, specifically procollagen maturation. While the annotation is correct, it is somewhat general given that HSP47 specifically assists procollagen maturation, not protein maturation broadly. Reason: HSP47 is essential for procollagen maturation, which is a form of protein maturation. The knockout data clearly shows accumulation of immature procollagen forms. While the term is broader than the actual function (which is collagen-specific), it correctly captures the biological process. Supporting Evidence: PMID:10995453 Hsp47 is an essential chaperone protein specific for collagen maturation and for normal mouse development file:mouse/Serpinh1/Serpinh1-deep-research-falcon.md HSP47 binds triple-helical procollagen in the ER and stabilizes the triple helix, thereby preventing unfolding and preventing aggregation within the ER lumen
GO:0051082 unfolded protein binding	IDA PMID:10862616 Conformational requirements of collagenous peptides for reco...	MODIFY	Summary: Unfolded protein binding is too broad for Serpinh1/Hsp47. The evidence supports collagen-specific protein folding chaperone activity in the ER. Reason: GO:0044183 protein folding chaperone is the better term for Hsp47 chaperoning procollagen triple-helix maturation. Proposed replacements: protein folding chaperone Supporting Evidence: file:mouse/Serpinh1/Serpinh1-notes.md HSP47 preferentially recognizes collagenous Gly-X-Y repeats in triple-helical conformation file:mouse/Serpinh1/Serpinh1-deep-research-falcon.md HSP47 binds triple-helical procollagen in the ER and stabilizes the triple helix
GO:0005515 protein binding	IPI PMID:10862616 Conformational requirements of collagenous peptides for reco...	REMOVE	Summary: This IPI annotation for generic protein binding derives from the same study (PMID:10862616) showing HSP47 interacts with collagenous peptides. The term 'protein binding' is uninformative -- the specific interaction is collagen binding (GO:0005518) which is already annotated. Per curation guidelines, 'protein binding' should be avoided in favor of more specific molecular function terms. Reason: 'Protein binding' is an uninformative term that does not convey the specific collagen-binding function of HSP47. The more informative GO:0005518 (collagen binding) is already annotated and better captures the molecular function. Per GO curation best practices, generic 'protein binding' should be replaced with specific binding terms. Supporting Evidence: file:mouse/Serpinh1/Serpinh1-deep-research-falcon.md A central feature of HSP47 is its sequence/structure selectivity for collagen triple helices.

Gene Description

Existing Annotations Review

Core Functions

Serpinh1/Hsp47 is an ER-resident collagen-specific protein folding chaperone that binds procollagen triple helices and is required for collagen maturation, collagen biosynthesis, and collagen fibril organization.

References

Deep Research

Falcon

OpenScientist

📚 Additional Documentation

Notes

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