Serpinh1

id: P19324
gene_symbol: Serpinh1
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:10090
  label: Mus musculus
description: >-
  Serpinh1 (also known as HSP47/Colligin/CBP1) is an ER-resident, collagen-specific
  molecular chaperone belonging to the serpin superfamily. Despite its serpin domain,
  HSP47 lacks protease inhibitor activity and instead functions exclusively as a
  substrate-specific chaperone for procollagens. It binds the triple-helical
  conformation of procollagen Gly-X-Y repeats in the ER, stabilizes the nascent
  triple helix to prevent premature denaturation and aggregation, and releases
  procollagen in a pH-dependent manner during ER-to-cis-Golgi transport. Hsp47
  knockout mice die before E11.5 with severe defects in collagen biosynthesis,
  fibril formation, and basement membrane integrity (PMID:10995453). HSP47 interacts
  with types I through V collagens in vitro, making it a broad collagen chaperone
  rather than a type-specific one. It is the first substrate-specific molecular
  chaperone identified in mammals.
existing_annotations:
- term:
    id: GO:0004867
    label: serine-type endopeptidase inhibitor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      HSP47/Serpinh1 is a member of the serpin superfamily by sequence homology
      and structural classification. The IBA annotation reflects the ancestral
      serpin function inferred phylogenetically. However, HSP47 has evolved to
      function exclusively 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. UniProt annotates the reactive bond homolog at residues 376-377
      but classifies this protein as a chaperone (KW: Chaperone), not as a
      protease inhibitor.
    action: REMOVE
    reason: >-
      Although HSP47 belongs to the serpin family by sequence and structure, it
      has lost protease inhibitor activity through evolution. Its function is
      exclusively as a collagen-specific chaperone. The IBA inference from the
      broader serpin family is incorrect for this particular member, which has
      neofunctionalized. The UniProt entry lists the KW 'Chaperone' but not
      'Serine protease inhibitor'.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:10995453
        supporting_text: >-
          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
      - reference_id: PMID:21606205
        supporting_text: >-
          Mia3 is present in regions demarcated by the ER-resident proteins
          calnexin and HSP47
- term:
    id: GO:0030199
    label: collagen fibril organization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    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).
    supported_by:
      - reference_id: PMID:10995453
        supporting_text: >-
          Though fibrillar structures were obviously evident at the periphery
          of neural tube and in the mesenchymal tissue
      - reference_id: PMID:22492985
        supporting_text: >-
          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
- term:
    id: GO:0004867
    label: serine-type endopeptidase inhibitor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    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.
    action: REMOVE
    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.
- term:
    id: GO:0005518
    label: collagen binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:10862616
        supporting_text: >-
          our results suggest that HSP47 preferentially recognizes collagenous
          Gly-X-Y repeats in triple-helical conformation
      - reference_id: PMID:10995453
        supporting_text: >-
          Hsp47 is unique in terms of its substrate specificity; that is, it
          binds exclusively to procollagens and collagens
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    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'.
    action: REMOVE
    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.
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    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.
    action: ACCEPT
    reason: >-
      Redundant with the IBA and IDA annotations for ER, but correctly
      reflects the biology. The ISO transfer from human is appropriate.
- term:
    id: GO:0005793
    label: endoplasmic reticulum-Golgi intermediate compartment
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:10995453
        supporting_text: >-
          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
- term:
    id: GO:0045121
    label: membrane raft
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Automatic transfer from human SERPINH1 via Ensembl Compara. Redundant
      with multiple other ER annotations but correct.
    action: ACCEPT
    reason: >-
      ER localization is well established. This IEA annotation provides
      additional orthology-based support consistent with all other evidence.
- term:
    id: GO:0005793
    label: endoplasmic reticulum-Golgi intermediate compartment
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      Automatic Ensembl Compara transfer. Redundant with the ISO annotation
      for the same term. Consistent with the transient ERGIC presence during
      collagen escort.
    action: ACCEPT
    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.
- term:
    id: GO:0045121
    label: membrane raft
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:22159717
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:28071719
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
- term:
    id: GO:0003433
    label: chondrocyte development involved in endochondral bone morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:22492985
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
      - reference_id: PMID:22492985
        supporting_text: >-
          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
- term:
    id: GO:0030199
    label: collagen fibril organization
  evidence_type: IMP
  original_reference_id: PMID:22492985
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:22492985
        supporting_text: >-
          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
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: ISO
  original_reference_id: PMID:23269685
  review:
    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.
    action: ACCEPT
    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.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:21606205
  review:
    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.
    action: ACCEPT
    reason: >-
      Direct experimental evidence from immunofluorescence demonstrating HSP47
      localization in the ER. This is the strongest evidence code among the
      multiple ER annotations.
    supported_by:
      - reference_id: PMID:21606205
        supporting_text: >-
          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
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:8018053
  review:
    summary: >-
      Shroff et al. (PMID:8018053) studied HSP47 expression in dental follicle
      cells during tooth eruption using immunofluorescence. They detected
      HSP47 in the cytoplasm of dental follicle cells, which is broadly
      consistent with its ER localization (the ER is within the cytoplasm).
      The term 'cytoplasm' is less specific than 'endoplasmic reticulum lumen'
      but not incorrect.
    action: ACCEPT
    reason: >-
      While 'cytoplasm' is a broader term than 'ER lumen', it is not incorrect
      since the ER is a cytoplasmic organelle. The immunofluorescence likely
      showed punctate ER staining that was described as cytoplasmic. The IDA
      evidence is valid even if less precise than later ER-specific annotations.
    supported_by:
      - reference_id: PMID:8018053
        supporting_text: >-
          Immunological probes were used here to investigate in vivo and in
          vitro the temporal and spatial expression of type I collagen and
          its molecular chaperone Hsp47 in the dental follicle during eruption
- term:
    id: GO:0030199
    label: collagen fibril organization
  evidence_type: IMP
  original_reference_id: PMID:10995453
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:10995453
        supporting_text: >-
          silver impregnation analysis was performed. Though fibrillar
          structures were obviously evident at the periphery of neural tube
          and in the mesenchymal tissue
      - reference_id: PMID:10995453
        supporting_text: >-
          only a limited number of collagen fibrils were observed in the
          lamina fibroreticularis and stroma
- term:
    id: GO:0032964
    label: collagen biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:10995453
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:10995453
        supporting_text: >-
          the mature, propeptide-cleaved α1(I) chain
      - reference_id: PMID:10995453
        supporting_text: >-
          This result demonstrated that Hsp47 functions as a molecular
          chaperone to ensure the rigid triple-helical conformation of type I
          collagen
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: IMP
  original_reference_id: PMID:10995453
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:10995453
        supporting_text: >-
          Hsp47 is an essential chaperone protein specific for collagen
          maturation and for normal mouse development
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:10862616
  review:
    summary: >-
      Koide et al. (PMID:10862616) demonstrated that HSP47 preferentially
      recognizes collagenous Gly-X-Y repeats in triple-helical conformation,
      not unfolded collagen chains. This is a critical distinction: HSP47
      binds the FOLDED (triple-helical) form of procollagen, not the unfolded
      form. This is unlike classical unfolded protein binding chaperones such
      as BiP/GRP78 which bind hydrophobic stretches of unfolded proteins.
      HSP47 stabilizes the triple helix to prevent its unwinding/denaturation,
      acting as a holdase for the folded conformation. The annotation
      GO:0051082 (unfolded protein binding) is therefore misleading. A more
      appropriate MF term would be GO:0044183 (protein folding chaperone),
      which is defined as 'Binding to a protein or a protein-containing
      complex to assist the protein folding process', or GO:0005518 (collagen
      binding) which directly describes the molecular interaction.
    action: MODIFY
    reason: >-
      The PMID:10862616 study explicitly shows that HSP47 recognizes the
      TRIPLE-HELICAL conformation of collagen, not unfolded protein. The
      abstract states HSP47 'preferentially recognizes collagenous Gly-X-Y
      repeats in triple-helical conformation'. The importance of substrate
      conformation was demonstrated by temperature-dependent binding (binding
      at 24C but not 30C, correlating with triple helix stability). HSP47 is
      therefore not an unfolded protein binder; it is a collagen-specific
      chaperone that binds the folded triple helix. GO:0044183 (protein
      folding chaperone) better captures the holdase/chaperone function.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
    supported_by:
      - reference_id: PMID:10862616
        supporting_text: >-
          our results suggest that HSP47 preferentially recognizes collagenous
          Gly-X-Y repeats in triple-helical conformation
      - reference_id: PMID:10862616
        supporting_text: >-
          Some peptides interacted with HSP47 at a lowered assay temperature
          at 24 degrees C but not at 30 degrees C, indicating the importance
          of conformational change of the substrate peptides
      - reference_id: PMID:10995453
        supporting_text: >-
          Hsp47 has been shown to interact preferentially with the
          triple-helical conformation of procollagens
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10862616
  review:
    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.
    action: REMOVE
    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.
# New annotations suggested
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IDA
  original_reference_id: PMID:10995453
  review:
    summary: >-
      HSP47 functions as a protein folding chaperone specific for collagen.
      The Hsp47 knockout study (PMID:10995453) demonstrated that without
      HSP47, type I collagen cannot form a rigid triple-helical structure.
      Procollagen secreted from Hsp47-/- cells showed the same protease
      sensitivity as heat-denatured collagen, and transfection of Hsp47 cDNA
      restored protease resistance. HSP47 binds the triple-helical form of
      procollagen to prevent its unwinding and ensures correct triple helix
      formation. GO:0044183 (protein folding chaperone) accurately describes
      this function.
    action: NEW
    reason: >-
      This term is not currently in the GO annotations for mouse Serpinh1
      but accurately describes its core molecular function. HSP47 is
      explicitly described as 'the first substrate-specific molecular
      chaperone to be identified in mammals' (PMID:10995453). The protein
      folding chaperone term captures its holdase/chaperone activity better
      than the current 'unfolded protein binding' annotation.
    supported_by:
      - reference_id: PMID:10995453
        supporting_text: >-
          This result demonstrated that Hsp47 functions as a molecular
          chaperone to ensure the rigid triple-helical conformation of type I
          collagen
      - reference_id: PMID:10995453
        supporting_text: >-
          Hsp47 is the first substrate-specific molecular chaperone to be
          identified in mammals
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000119
  title: Automated transfer of experimentally-verified manual GO annotation data to
    mouse-human orthologs
  findings: []
- id: PMID:10862616
  title: Conformational requirements of collagenous peptides for recognition by the
    chaperone protein HSP47.
  findings:
    - statement: HSP47 preferentially recognizes collagenous Gly-X-Y repeats in triple-helical
        conformation
      supporting_text: >-
        our results suggest that HSP47 preferentially recognizes collagenous
        Gly-X-Y repeats in triple-helical conformation
    - statement: Temperature-dependent binding indicates importance of substrate triple helix
        conformation
      supporting_text: >-
        Some peptides interacted with HSP47 at a lowered assay temperature
        at 24 degrees C but not at 30 degrees C, indicating the importance
        of conformational change of the substrate peptides
- id: PMID:10995453
  title: Embryonic lethality of molecular chaperone hsp47 knockout mice is associated
    with defects in collagen biosynthesis.
  findings:
    - statement: Hsp47 knockout causes embryonic lethality before 11.5 dpc
      supporting_text: >-
        Homozygosity for the Hsp47 mutation resulted in embryonic lethality
    - statement: Mature propeptide-cleaved alpha1(I) collagen is absent in knockout mice
      supporting_text: >-
        the mature, propeptide-cleaved α1(I) chain
    - statement: Collagen secreted from Hsp47-/- cells has abnormal triple helix (protease-sensitive)
      supporting_text: >-
        collagens with an abnormal triple helix are secreted
    - statement: Transfection of Hsp47 cDNA restores collagen triple helix formation
      supporting_text: >-
        the secreted collagen became resistant to protease treatment
    - statement: HSP47 is the first substrate-specific molecular chaperone identified in mammals
      supporting_text: >-
        Hsp47 is the first substrate-specific molecular chaperone to be
        identified in mammals
    - statement: Collagen fibrils and basement membranes are severely deficient in knockout mice
      supporting_text: >-
        Collagen fibers and basement membranes were hardly detected in
        knockout mice
- id: PMID:21606205
  title: Global defects in collagen secretion in a Mia3/TANGO1 knockout mouse.
  findings:
    - statement: HSP47 confirmed as ER-resident by immunofluorescence colocalization with
        calnexin in primary chondrocytes and MEFs
      supporting_text: >-
        Mia3 is present in regions demarcated by the ER-resident proteins
        calnexin and HSP47
    - statement: HSP47 used as ER marker in colocalization studies
      supporting_text: >-
        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
- id: PMID:22159717
  title: 'The matrisome: in silico definition and in vivo characterization by proteomics
    of normal and tumor extracellular matrices.'
  findings:
    - statement: HSP47 detected in ECM-enriched fractions by mass spectrometry (likely
        co-purifying with collagen substrates)
- id: PMID:22492985
  title: The molecular chaperone Hsp47 is essential for cartilage and endochondral
    bone formation.
  findings:
    - statement: Conditional Hsp47 knockout in chondrocytes causes severe chondrodysplasia
      supporting_text: >-
        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
    - statement: Type II and XI collagen levels reduced in conditional knockout
      supporting_text: >-
        exhibited severe generalized chondrodysplasia and bone deformities
        with lower levels of type II and type XI collagen
    - statement: Misaligned type I collagen molecules accumulate
      supporting_text: >-
        Second-harmonic generation (SHG) analysis and electron microscopy
        revealed the accumulation of misaligned type I collagen molecules
        in the intervertebral discs
    - statement: Endochondral bones severely twisted and shortened
      supporting_text: >-
        the endochondral bones were severely twisted and shortened
- id: PMID:23269685
  title: Role for phospholipid flippase complex of ATP8A1 and CDC50A proteins in cell
    migration.
  findings:
    - statement: HSP47 used as reference for ER localization in ISO annotation transfer
- id: PMID:28071719
  title: Quantitative proteomic profiling of the extracellular matrix of pancreatic
    islets during the angiogenic switch and insulinoma progression.
  findings:
    - statement: HSP47 detected in ECM-enriched fractions from pancreatic islets
- id: PMID:8018053
  title: Dynamic variations in the expression of type I collagen and its molecular
    chaperone Hsp47 in cells of the mouse dental follicle during tooth eruption.
  findings:
    - statement: HSP47 expression correlates with type I collagen production in dental follicle
      supporting_text: >-
        The production of type I collagen and Hsp47 in the follicle varied
        with the stage of dental development and eruption
    - statement: Immunolocalization shows HSP47 in cytoplasm of dental follicle cells
      supporting_text: >-
        Immunological probes were used here to investigate in vivo and in
        vitro the temporal and spatial expression of type I collagen and
        its molecular chaperone Hsp47 in the dental follicle during eruption
core_functions:
  - molecular_function:
      id: GO:0044183
      label: protein folding chaperone
    description: >-
      HSP47 is a collagen-specific protein folding chaperone. It binds the
      triple-helical conformation of procollagen in the ER lumen, stabilizes the
      nascent triple helix to prevent denaturation, and ensures correct folding.
      Without HSP47, collagen cannot form rigid triple helices (PMID:10995453).
    directly_involved_in:
      - id: GO:0032964
        label: collagen biosynthetic process
    locations:
      - id: GO:0005788
        label: endoplasmic reticulum lumen
  - molecular_function:
      id: GO:0005518
      label: collagen binding
    description: >-
      HSP47 specifically and transiently binds to procollagen/collagen,
      recognizing Gly-X-Y repeats in the triple-helical conformation
      (PMID:10862616). It interacts with types I-V collagens.
    directly_involved_in:
      - id: GO:0030199
        label: collagen fibril organization
    locations:
      - id: GO:0005788
        label: endoplasmic reticulum lumen