COL9A1 encodes the alpha1 chain of collagen IX, a fibril-associated collagen with interrupted triple helices in cartilage and vitreous extracellular matrix. Alpha1(IX) assembles with alpha2(IX) and alpha3(IX), and the resulting heterotrimer associates with type II collagen fibrils and other matrix components. The long alpha1 chain exposes an N-terminal NC4 domain that binds heparin and cartilage oligomeric matrix protein. Recombinant NC4 can also inhibit terminal complement assembly. Alternative transcripts encode a shorter N-terminal form and a truncated product. Biallelic pathogenic variants cause recessive Stickler syndrome with ocular, auditory and skeletal manifestations.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:15047691 Characterization of recombinant amino-terminal NC4 domain of... | MODIFY | Reason: The original study directly tested recombinant human NC4 with rat COMP, whose P35444 accession is explicitly named in Methods, including full COMP and its 266β755 fragment. COMP is an extracellular matrix constituent, so refine the positive interaction to extracellular matrix binding. Preserve the mixed-species partner and heparin-competition scope; this is not a new adaptor mechanism or evidence for equal activity of every natural COL9A1 product. The refinement is semantic ligand specificity, not a claimed current is_a edge from protein binding. Proposed replacements: extracellular matrix binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Reason: Retain the positive association with the exact 236-residue GIPC1 isoform O14908-2, reconstructed from its recorded N-terminal deletion and matched to all three array, pooling and validated two-hybrid records. The canonical PDZ-containing identity and possible G-protein-linked context do not resolve a more specific binding activity for this pair. Yeast assay positivity is retained without a native cellular pathway, PDZ-interface or isoform-specific signaling claim. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MODIFY | Reason: Three positive two-hybrid records match canonical 173-residue CRYAA. Its official experimental functional annotation establishes a protein chaperone that prevents aggregation; GO:0051087 names binding to that partner class. Refine the accepted interaction without asserting that COL9A1 itself folds proteins or that this screen measured a folding reaction. The human products were tested in yeast, and natural colocalization or a specific contact interface was not established. Proposed replacements: protein-folding chaperone binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MODIFY | Reason: Three positive two-hybrid records match the 244-residue KLK6 precursor. Official identity and direct activity annotations establish its serine-protease class, fitting protease binding more specifically than enzyme binding. Preserve the precursor and assay scope: processing, active-enzyme state, substrate cleavage and the contacted region were not measured in these records. The caspase and ubiquitin-specific-protease children do not describe KLK6. Proposed replacements: protease binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Reason: The positive association has a verified collagen counterpart, canonical human COL6A1/P12109. Two exact anti-tag affinity-purification records occur in HEK293T and HCT116 contexts; one is a spoke-expanded complex association. Collagen binding narrows the partner class while preserving AP-MS/co-complex evidence. It does not claim isolated binary affinity, native cartilage contact or a specific multichain topology. Proposed replacements: collagen binding Supporting Evidence: |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2089971 | ACCEPT | Reason: The secretion event includes both luminal precursor input and extracellular collagen output; this assertion concerns the destination. The actual event summary and typed participant path to P20849 were inspected. Retain this source-specific extracellular location; underlying event citations were not all independently recovered. Supporting Evidence: Reactome:R-HSA-2089971 |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2213210 | ACCEPT | Reason: The event specifically places collagen IX at the surface of type II fibrils through covalent cross-links, consistent with the human cartilage source. The actual event summary and typed participant path to P20849 were inspected. Retain this source-specific extracellular location; underlying event citations were not all independently recovered. Supporting Evidence: Reactome:R-HSA-2213210 |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2327695 | ACCEPT | Reason: The event contains extracellular collagen IX within the integrin alpha1beta1/alpha2beta1 ligand set; participant membership is not an isolated alpha1-chain affinity assay for every integrin. The actual event summary and typed participant path to P20849 were inspected. Retain this source-specific extracellular location; underlying event citations were not all independently recovered. Supporting Evidence: Reactome:R-HSA-2327695 |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-375151 | ACCEPT | Reason: The NCAM1 event includes collagen IX as an extracellular ligand context, without assigning neural adhesion machinery activity to the alpha1 chain. The actual event summary and typed participant path to P20849 were inspected. Retain this source-specific extracellular location; underlying event citations were not all independently recovered. Supporting Evidence: Reactome:R-HSA-375151 |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-382054 | ACCEPT | Reason: The PDGF event places collagen-containing matrix among growth-factor retention partners; this does not make COL9A1 a PDGF receptor or establish an isolated chain-specific binding constant. The actual event summary and typed participant path to P20849 were inspected. Retain this source-specific extracellular location; underlying event citations were not all independently recovered. Supporting Evidence: Reactome:R-HSA-382054 |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-4084903 | ACCEPT | Reason: The alpha10beta1 integrin event includes extracellular collagen IX material, with the chain represented through its complex. The actual event summary and typed participant path to P20849 were inspected. Retain this source-specific extracellular location; underlying event citations were not all independently recovered. Supporting Evidence: Reactome:R-HSA-4084903 |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-4086223 | ACCEPT | Reason: The alpha11beta1 event explicitly concerns extracellular collagen IX ligand material; the complex-level ligand description is not an all-isoform assay. The actual event summary and typed participant path to P20849 were inspected. Retain this source-specific extracellular location; underlying event citations were not all independently recovered. Supporting Evidence: Reactome:R-HSA-4086223 |
| GO:0005594 collagen type IX trimer | IBA GO_REF:0000033 | ACCEPT | Reason: The canonical alpha1(IX)/alpha2(IX)/alpha3(IX) heterotrimer fits the exact current type IX definition and direct target assembly evidence. The target appearing as its own PAINT descendant source is expected, not circular. Current same-term target records corroborate the placement; the historical ancestral node/tree was not reconstructed. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002770847 UNRESOLVED Historical IBD/node/tree inspection is unresolved. Current donor/target corroboration and direct target biology support the reviewed annotation independently; no ancestral placement error is asserted. |
| GO:0005594 collagen type IX trimer | IDA PMID:8660302 Collagen type IX from human cartilage: a structural profile ... | ACCEPT | Reason: Original human cartilage analysis identifies type IX chains and maps native type IIβIX and IXβIX cross-links. Retain alpha1(IX) membership in the defined heterotrimer, separating those native network observations from recombinant constructs and from an alpha1βalpha1 homodimer claim. Supporting Evidence: |
| GO:0005594 collagen type IX trimer | IPI PMID:27897211 Structural insight for chain selection and stagger control i... | ACCEPT | Reason: The actual structure assembles alpha1/alpha2/alpha3 IX NC2 chains attached to engineered type I collagen hostβguest triple-helical sequences. It establishes a target-chain trimerization/stagger interface consistent with type IX membership. It is not a structure of intact collagen IX or proof that the truncated natural product retains assembly competence. Supporting Evidence: PMID:27897211 Three unique chains form a parallel Ξ±-helical right-handed bundle. |
| GO:0005594 collagen type IX trimer | TAS PMID:9707347 Human COL9A1 and COL9A2 genes. Two genes of 90 and 15 kb cod... | ACCEPT | Reason: Retain established type IX heterotrimer membership with curator deference and independent assembly evidence. The complete authentic cited abstract establishes human COL9A1/COL9A2 gene and alternative-exon structure; its full text was not recovered, so it is not described as a newly read purified assembly experiment. |
| GO:0005788 endoplasmic reticulum lumen | IEA GO_REF:0000117 | KEEP AS NON CORE | Reason: The signal-bearing precursor enters the ER lumen for chain assembly before secretion. Current ARBA00028691 still emits this term, and its IPR008160/IPR013320/Primates branch matches the current official target record. This corroborates a biosynthetic compartment rather than a mature-matrix core location or a chaperone/catalytic activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00028691 SUPPORTS TRANSFER Current exact rule output and target-matching condition branch inspected; ER-luminal precursor biology is independently supported. Supporting Evidence: Reactome:R-HSA-2022073 Reactome:R-HSA-8944229 |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-2022073 | KEEP AS NON CORE | Reason: The triple-helix formation event places collagen precursors in the ER lumen while other proteins perform hydroxylation/isomerization and chaperone functions. Retain the precursor location outside the principal extracellular core; actual event membership was traced without importing other participants' catalytic functions. Supporting Evidence: Reactome:R-HSA-2022073 |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-2089971 | KEEP AS NON CORE | Reason: The secretion event has an ER-luminal precursor input, distinct from its extracellular output reviewed separately. Retain the precursor location outside the principal extracellular core; actual event membership was traced without importing other participants' catalytic functions. Supporting Evidence: Reactome:R-HSA-2089971 |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8944229 | KEEP AS NON CORE | Reason: The type IX chain-association event places the precursor complex in the ER lumen. Its general C-terminal-propeptide narrative must not obscure direct IX evidence for NC2 and additional domain contributions. Retain the precursor location outside the principal extracellular core; actual event membership was traced without importing other participants' catalytic functions. Supporting Evidence: Reactome:R-HSA-8944229 |
| GO:0009887 animal organ morphogenesis | IEA GO_REF:0000117 | UNDECIDED | Reason: Current ARBA00028067 emits animal organ morphogenesis and its exact FunFam 2.60.120.200:FF:000105 branch 83 matches the official target record. The present rule premise is real. Its biological specificity remains unresolved: the bounded evidence does not identify a performed organ-morphogenesis contribution, while extracellular structural work could in principle contribute. The narrower 1987 TAS citation is assessed separately; neither that paper nor the current match reconstructs the historical rule training/assignment. Propagation Review Root cause: UNRESOLVED Sources checked: ARBA:ARBA00028067 UNRESOLVED Exact current FunFam branch83 and output are verified; the biological specificity of the organ-morphogenesis transfer and its historical derivation remain unresolved. No absent-rule, wrong-family or historical-misassignment claim. Supporting Evidence: |
| GO:0009887 animal organ morphogenesis | TAS PMID:3473493 Structure of the glycosaminoglycan domain in the type IX col... | MARK AS OVER ANNOTATED | Reason: The complete original five-page article studies chicken embryonic cartilage cDNA/genomic sequences and purified collagen fragments, including genuine alpha1/alpha2 NC3 comparisons. It explains molecular structure and the glycosaminoglycan attachment sequence, but does not establish a step in generating or organizing an animal organ. This source-specific process attribution is over-extended; the judgment does not deny COL9A1 structural contributions to development and is not a wrong-gene conclusion from the alpha2-focused abstract. Supporting Evidence: |
| GO:0030020 extracellular matrix structural constituent conferring tensile strength | IBA GO_REF:0000033 | ACCEPT | Reason: Retain the structural interpretation under the current GO term's explicit permission for extracellular matrix collagen proteins and the target's fibril-associated chain/cross-link evidence. The phylogenetic assertion is not judged by donor count or pairwise similarity; current descendant records corroborate collagen structural biology while historical node placement remains uninspected. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001166351 UNRESOLVED Historical IBD/node/tree inspection is unresolved. Current donor/target corroboration and direct target biology support the reviewed annotation independently; no ancestral placement error is asserted. |
| GO:0030020 extracellular matrix structural constituent conferring tensile strength | IC PMID:8660302 Collagen type IX from human cartilage: a structural profile ... | ACCEPT | Reason: Native human alpha1(IX)-containing collagen IX participates in covalent links with the type II/IX matrix. The collagen convention supports the structural inference from type IX membership. This is fibril-associated matrix contribution, not an isolated tensile-force measurement or autonomous fibrillar-collagen assembly. Supporting Evidence: |
| GO:0030020 extracellular matrix structural constituent conferring tensile strength | RCA PMID:25037231 Extracellular matrix signatures of human primary metastatic ... | ACCEPT | Reason: Retain the structural collagen interpretation while distinguishing it from what the source measured. Actual human ECM-enrichment/MS Methods and original supplementary row121 identify a grouped COL9A1 entry labeled Isoform Short. The RCA classification and established collagen biology support the structural term; mass-spectrometric detection itself does not measure tensile mechanics or isolate a natural product's activity. |
| GO:0030198 extracellular matrix organization | IBA GO_REF:0000033 | ACCEPT | Reason: Alpha1(IX) contributes physical chain interfaces and matrix cross-links that organize the extracellular matrix, fitting the existing process definition. Direct human cartilage and engineered assembly evidence corroborate the inherited matrix role. Current donor identities and same-term records were traced without reconstructing the historical PAINT tree or treating a small source set as weak evidence. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002770636 UNRESOLVED Historical IBD/node/tree inspection is unresolved. Current donor/target corroboration and direct target biology support the reviewed annotation independently; no ancestral placement error is asserted. |
| GO:0030246 carbohydrate binding | EXP PMID:15047691 Characterization of recombinant amino-terminal NC4 domain of... | MODIFY | Reason: Original human NC4 surface-plasmon-resonance and solid-phase assays directly measure heparin binding. Replace the generic carbohydrate term with heparin binding at the observed ligand scope. This is a semantic refinement, not an assertion that the current typed ontology places heparin binding under carbohydrate binding; equivalence among natural splice products is not inferred. Proposed replacements: heparin binding Supporting Evidence: PMID:15047691 specifically binds heparin |
| GO:0030246 carbohydrate binding | IMP PMID:15047691 Characterization of recombinant amino-terminal NC4 domain of... | MODIFY | Reason: The original NC4 mutagenesis and competition experiments map heparin binding, including the N-terminal basic region. Replace the generic carbohydrate term with heparin binding at the observed ligand scope. This is a semantic refinement, not an assertion that the current typed ontology places heparin binding under carbohydrate binding; equivalence among natural splice products is not inferred. Proposed replacements: heparin binding Supporting Evidence: |
| GO:0030246 carbohydrate binding | IPI PMID:15047691 Characterization of recombinant amino-terminal NC4 domain of... | MODIFY | Reason: The original IPI assertion names the glycosaminoglycan partner; retain that source field while naming the directly tested heparin ligand. Replace the generic carbohydrate term with heparin binding at the observed ligand scope. This is a semantic refinement, not an assertion that the current typed ontology places heparin binding under carbohydrate binding; equivalence among natural splice products is not inferred. Proposed replacements: heparin binding Supporting Evidence: |
| GO:0030246 carbohydrate binding | IPI PMID:17553797 Crystal structure of the N-terminal NC4 domain of collagen I... | MODIFY | Reason: The complete authentic abstract explicitly reports an NC4 heparin-tetrasaccharide NMR interaction. Full original Methods were not recovered, so exact construct boundaries and further controls are not claimed. Replace the generic carbohydrate term with heparin binding at the observed ligand scope. This is a semantic refinement, not an assertion that the current typed ontology places heparin binding under carbohydrate binding; equivalence among natural splice products is not inferred. Proposed replacements: heparin binding Supporting Evidence: |
| GO:0031012 extracellular matrix | HDA PMID:25037231 Extracellular matrix signatures of human primary metastatic ... | ACCEPT | Reason: Actual ECM-enriched human normal/tumor colon and liver samples contain a grouped COL9A1 protein entry in original supplementary row121 of both complete and matrisome sheets. Its principal accession is P20849-2, with other COL9A1 products in the group. Retain extracellular matrix location, without claiming isoform-exclusive peptides, disease-specific causality or every sample being positive. Supporting Evidence: |
| GO:0031012 extracellular matrix | IBA GO_REF:0000033 | ACCEPT | Reason: The extracellular matrix location is independently supported by native human cartilage chain/cross-link work and human ECM proteomics. Current donor identities and literal records corroborate the inherited localization. The target is a legitimate source of its own PAINT inference; neither that self-entry nor donor count is a reason to reject the placement. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008390299 UNRESOLVED Historical IBD/node/tree inspection is unresolved. Current donor/target corroboration and direct target biology support the reviewed annotation independently; no ancestral placement error is asserted. |
| GO:0042803 protein homodimerization activity | IPI PMID:8660302 Collagen type IX from human cartilage: a structural profile ... | KEEP AS NON CORE | Reason: Retain contextual self-association with the two sources distinguished. The original human cartilage paper maps alpha1(IX) links to type II and alpha3(IX) NC1 rather than independently resolving an alpha1βalpha1 homodimer. Separately, actual PMID:17880280 Results report predominantly monomers and dimers when full-length human alpha1(IX) is expressed individually in insect cells. This supports a non-core recombinant dimer context, not a native homodimer core or equal activity of all natural products. The public source-evidence index, followup_source_clarifications, provides the original postprint Results/Figure 3 locator and a short literal excerpt; the unchanged normal abstract is not the source of this dimer observation. |
| GO:0001971 negative regulation of activation of membrane attack complex | IDA PMID:21659506 NC4 Domain of cartilage-specific collagen IX inhibits comple... | NEW | Reason: Recombinant human alpha1(IX) NC4 directly inhibits purified C9 polymerization and reduces cell-associated polymeric C9 with appropriate positive/negative controls and accompanying hemolysis assays. The domain performs inhibitory work at terminal-complement assembly; this is not inferred from precursor necessity or a downstream knockout effect. The pAM104-2 human NC4 construct is authenticated through original PMID:19700767 Methods; exact residue endpoints were not resolved. Restrict the assertion to the tested recombinant domain, not intact collagen IX, every splice product or a demonstrated endogenous immune role. NC4 is not itself a factor-I cofactor or protease, although it enhances reactions containing FH/C4BP. Current typed coverage has no overlap with original or replacement terms; same-role CLU carries direct IDA1971, while VTN/COMP exact-query absences are retained. No redundant parent or complement-binding NEW is proposed. Supporting Evidence: PMID:21659506 NC4 inhibited C9 polymerization in a concentration-dependent manner |
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Download this section (compressed HTML)Q: Which COL9A1 products enter native type IX heterotrimers in cartilage and vitreous, and can the truncated NC4-containing product be secreted or act independently?
Q: How do NC4 heparin and matrix-partner interactions contribute to fibril organization in native tissue, relative to the separate collagenous cross-links?
Q: Does native or proteolytically released human NC4 inhibit terminal complement under tissue concentrations, and how do C9 binding and enhanced FH/C4BP-dependent reactions contribute separately?
Q: What performed organ-morphogenesis contribution supports the current matching ARBA rule, beyond the separate 1987 sequence-characterization paper and known matrix assembly?
Q: What is the biological significance of the weak NC4 zinc affinity reported in solution, and which intact products retain that interaction?
Experiment: Express sequence-defined natural COL9A1 products with human alpha2(IX)/alpha3(IX), then separately measure secretion, chain stoichiometry, collagen folding and matrix incorporation.
Hypothesis: The short precursor retains major assembly regions whereas the truncated product has a distinct extracellular fate.
Experiment: Compare intact type IX, released sequence-defined NC4 and NC4 ligand-site mutants in human complement assays with purified C9 and separately reconstituted FI/FH/C4BP reactions.
Hypothesis: Direct terminal-complement inhibition can be separated from effects on other complement cofactors.
Experiment: Combine COL9A1 loss and product-specific rescue with quantitative developmental tissue architecture and matched matrix abundance controls.
Hypothesis: A performed morphogenetic structural step can be distinguished from correlated expression or generalized tissue damage.
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