COL4A5

Summary: Specify the collagen matrix tensile-strength class.

Reason: The collagen-domain mapping is consistent with alpha-5 participation in basement-membrane networks. The current GO:0030020 comment explicitly permits extracellular-matrix collagen proteins; actual human NC1 self-assembly and established type-IV protomer organization support that structural classification. This is not a claim of an isolated-chain force assay or equivalent activity of both alternative products.

Proposed replacements: extracellular matrix structural constituent conferring tensile strength

Summary: Retain the modeled extracellular region location.

Reason: Authenticated event R-HSA-1454757 (Gelatin degradation by MMP1, 2, 3, 7, 8, 9, 12, 13) resolves P29400 through 72 enumerated target paths. A representative input route reaches 3x4Hyp-3Hyp-GalHyl-COL4A5(27-?) [extracellular region]. The precursor in the ER lumen and extracellular matrix entities are distinguished. The chain supplies structure or is bound/processed in these reactions; this cellular-component assertion does not assign the modifying enzyme, receptor or trafficking activity to collagen.

Summary: Retain the modeled extracellular region location.

Reason: Authenticated event R-HSA-1564142 (Collagen type IV degradation by MMP2,3,4,9,10,12) resolves P29400 through 96 enumerated target paths. A representative input route reaches 3x4Hyp-3Hyp-GalHyl-COL4A5 [extracellular region]. The precursor in the ER lumen and extracellular matrix entities are distinguished. The chain supplies structure or is bound/processed in these reactions; this cellular-component assertion does not assign the modifying enzyme, receptor or trafficking activity to collagen.

Summary: Retain the modeled extracellular region location.

Reason: Authenticated event R-HSA-2213207 (Formation of collagen networks) resolves P29400 through 36 enumerated target paths. A representative input route reaches 3x4Hyp-3Hyp-GalHyl-COL4A5 [extracellular region]. The precursor in the ER lumen and extracellular matrix entities are distinguished. The chain supplies structure or is bound/processed in these reactions; this cellular-component assertion does not assign the modifying enzyme, receptor or trafficking activity to collagen.

Summary: Retain the modeled extracellular region location.

Reason: Authenticated event R-HSA-2327695 (Collagen types III, IV, V, VI, VIII, IX, XVI bind integrins alpha1beta1 and alpha2beta1) resolves P29400 through 48 enumerated target paths. A representative input route reaches 3x4Hyp-3Hyp-GalHyl-COL4A5 [extracellular region]. The precursor in the ER lumen and extracellular matrix entities are distinguished. The chain supplies structure or is bound/processed in these reactions; this cellular-component assertion does not assign the modifying enzyme, receptor or trafficking activity to collagen.

Summary: Retain the modeled extracellular region location.

Reason: Authenticated event R-HSA-2327733 (FN1 binds Collagen types I-V, VII) resolves P29400 through 48 enumerated target paths. A representative input route reaches 3x4Hyp-3Hyp-GalHyl-COL4A5 [extracellular region]. The precursor in the ER lumen and extracellular matrix entities are distinguished. The chain supplies structure or is bound/processed in these reactions; this cellular-component assertion does not assign the modifying enzyme, receptor or trafficking activity to collagen.

Summary: Retain the modeled extracellular region location.

Reason: Authenticated event R-HSA-2327738 (DDR1 binds collagen type I, II, III, IV, V, XI fibrils) resolves P29400 through 48 enumerated target paths. A representative input route reaches 3x4Hyp-3Hyp-GalHyl-COL4A5 [extracellular region]. The precursor in the ER lumen and extracellular matrix entities are distinguished. The chain supplies structure or is bound/processed in these reactions; this cellular-component assertion does not assign the modifying enzyme, receptor or trafficking activity to collagen.

Summary: Retain the modeled extracellular region location.

Reason: Authenticated event R-HSA-2396234 (Collagen type VII binds laminin-322 and collagen IV) resolves P29400 through 24 enumerated target paths. A representative input route reaches 3x4Hyp-3Hyp-GalHyl-COL4A5 [extracellular region]. The precursor in the ER lumen and extracellular matrix entities are distinguished. The chain supplies structure or is bound/processed in these reactions; this cellular-component assertion does not assign the modifying enzyme, receptor or trafficking activity to collagen.

Summary: Retain the modeled extracellular region location.

Reason: Authenticated event R-HSA-2426450 (Laminins:Nidogens binds collagen type IV networks) resolves P29400 through 48 enumerated target paths. A representative input route reaches 3x4Hyp-3Hyp-GalHyl-COL4A5 [extracellular region]. The precursor in the ER lumen and extracellular matrix entities are distinguished. The chain supplies structure or is bound/processed in these reactions; this cellular-component assertion does not assign the modifying enzyme, receptor or trafficking activity to collagen.

Summary: Retain the modeled extracellular region location.

Reason: Authenticated event R-HSA-2559639 (Collagen type IV sulfilimine cross-linking by peroxidasin) resolves P29400 through 93 enumerated target paths. A representative input route reaches 3x4Hyp-3Hyp-GalHyl-COL4A5 [extracellular region]. The precursor in the ER lumen and extracellular matrix entities are distinguished. The chain supplies structure or is bound/processed in these reactions; this cellular-component assertion does not assign the modifying enzyme, receptor or trafficking activity to collagen.

Summary: Retain the modeled extracellular region location.

Reason: Authenticated event R-HSA-375151 (Interaction of NCAM1 with collagens) resolves P29400 through 2 enumerated target paths. A representative input route reaches COL4A5(27-?) [extracellular region]. The precursor in the ER lumen and extracellular matrix entities are distinguished. The chain supplies structure or is bound/processed in these reactions; this cellular-component assertion does not assign the modifying enzyme, receptor or trafficking activity to collagen.

Summary: Retain the modeled extracellular region location.

Reason: Authenticated event R-HSA-382054 (PDGF binds to extracellular matrix proteins) resolves P29400 through 2 enumerated target paths. A representative input route reaches COL4A5(27-?) [extracellular region]. The precursor in the ER lumen and extracellular matrix entities are distinguished. The chain supplies structure or is bound/processed in these reactions; this cellular-component assertion does not assign the modifying enzyme, receptor or trafficking activity to collagen.

Summary: Retain the modeled extracellular region location.

Reason: Authenticated event R-HSA-9638628 (DraE binds Collagen IV) resolves P29400 through 48 enumerated target paths. A representative input route reaches 3x4Hyp-3Hyp-GalHyl-COL4A5 [extracellular region]. The precursor in the ER lumen and extracellular matrix entities are distinguished. The chain supplies structure or is bound/processed in these reactions; this cellular-component assertion does not assign the modifying enzyme, receptor or trafficking activity to collagen.

Summary: Retain the modeled extracellular region location.

Reason: Authenticated event R-NUL-4084497 (Collagen VII binds collagen IV) resolves P29400 through 24 enumerated target paths. A representative input route reaches 3x4Hyp-3Hyp-GalHyl-COL4A5 [extracellular region]. The precursor in the ER lumen and extracellular matrix entities are distinguished. The chain supplies structure or is bound/processed in these reactions; this cellular-component assertion does not assign the modifying enzyme, receptor or trafficking activity to collagen. This is a chimeric event with human collagen-IV entities and mouse collagen-VII context, not a new all-human interaction experiment.

Summary: Specify the type-IV collagen trimer.

Reason: The original InterPro-derived collagen-trimer class can be refined to the established type-IV protomer. The current GO:0005587 definition describes the network-forming class; its alpha1/alpha2 example does not exclude alpha5-containing protomers. The available PMID:12193605 abstract supports alpha3/alpha4/alpha5 organization, while actual human alpha5 NC1 self-assembly provides separate domain-level structural evidence. The latter experiment did not reconstruct a native alpha345 heterotrimer.

Proposed replacements: collagen type IV trimer

Summary: Retain the inherited type-IV complex identity.

Reason: Current exact-term records for the resolved mouse Col4a3/Col4a2/Col4a5 and human COL4A2 descendants provide source context. The alpha5-containing type-IV protomer is independently supported. The historical PAINT alignment and PTN009074934 placement were not reconstructed, so the current records are not represented as a newly inspected ancestral assertion. Donor count is not a criterion for rejecting the inference.

Summary: Retain the conserved type-IV trimer assignment.

Reason: The exact Q63ZW6/Ensembl donor resolves to mouse Col4a5 and carries a current IDA trimer record from PMID:12101409. That abstract concerns KLF5 and does not expose the alpha5 assay; it is not claimed as an independently verified construct experiment or rejected for its title. Independent alpha5 structural/complex evidence supports the human term while the original donor-source detail remains unverified.

Summary: Retain the independently established type-IV trimer identity.

Reason: The complete available PMID:29853175 abstract describes fibril assembly generally and does not reveal the alpha5-specific passage. Established alpha5-containing type-IV protomers independently support this complex term. Preserve the original NAS source and mark its precise citation link unverified rather than infer a wrong-gene attribution from the abstract.

Summary: Retain the type-IV collagen complex class.

Reason: The original human Alport abstract identifies COL4A5 as a major glomerular-basement-membrane component and reports mutations in affected kindreds. It is clinical/genetic context rather than a direct chain-stoichiometry experiment. Independent type-IV organization and alpha5 NC1 assembly support the retained trimer classification.

Summary: Retain direct human basement-membrane localization.

Reason: The complete original abstract describes peptide-specific monoclonal antibodies and differential alpha5/alpha6 staining in human kidney, skin and other tissues. Alpha5 appears in glomerular basement membrane, whereas alpha6 is absent there in that assay. This supports location without treating colocalization elsewhere as proof of a particular heterotrimer stoichiometry.

Summary: Retain human intestinal basement-membrane localization.

Reason: The original study uses immunofluorescence, Western blotting, transcript analysis and human fetal intestinal graft/culture models. Alpha5 is associated with the epithelial basement membrane during development and reduced in adult intestine. The authors suggest an alpha5/alpha6 heterotrimer; that suggestion is not relabeled as direct stoichiometric assembly evidence.

Summary: Retain the composite basement-membrane location.

Reason: Direct human localization and current exact mouse donor records support this location. The composite source also lists ARBA00027708 and SL-0025. The retrieved rule has a Glires collagen branch that does not match human, and its target FunFam alternatives were not established. No current-rule activation is asserted merely from the historic source label; independent human evidence supports the retained annotation.

Summary: Retain the ER-lumen biosynthetic location.

Reason: The secreted chain is represented as an ER-lumen precursor in authenticated type-IV association, folding and secretion routes. Current ARBA00028691 includes an IPR050149/PTHR24023:SF1082 branch, whereas the official target is SF1019; matching the domain alone does not establish that branch. Other target FunFam routes remain unresolved. Retention is supported independently by precursor biology and the exact Reactome entity paths, not a claimed successful reconstruction of the historical rule.

Summary: Retain the modeled endoplasmic reticulum lumen location.

Reason: Authenticated event R-HSA-2022073 (Procollagen triple helix formation) resolves P29400 through 72 enumerated target paths. A representative input route reaches 3x4Hyp-3Hyp-GalHyl-COL4A5 [endoplasmic reticulum lumen]. The precursor in the ER lumen and extracellular matrix entities are distinguished. The chain supplies structure or is bound/processed in these reactions; this cellular-component assertion does not assign the modifying enzyme, receptor or trafficking activity to collagen.

Summary: Retain the modeled endoplasmic reticulum lumen location.

Reason: Authenticated event R-HSA-2089971 (Secretion of collagens) resolves P29400 through 36 enumerated target paths. A representative input route reaches 3x4Hyp-3Hyp-GalHyl-COL4A5 [endoplasmic reticulum lumen]. The precursor in the ER lumen and extracellular matrix entities are distinguished. The chain supplies structure or is bound/processed in these reactions; this cellular-component assertion does not assign the modifying enzyme, receptor or trafficking activity to collagen.

Summary: Retain the modeled endoplasmic reticulum lumen location.

Reason: Authenticated event R-HSA-8944265 (Association of procollagen type IV) resolves P29400 through 72 enumerated target paths. A representative input route reaches 3x4Hyp-3Hyp-GalHyl-COL4A5 [endoplasmic reticulum lumen]. The precursor in the ER lumen and extracellular matrix entities are distinguished. The chain supplies structure or is bound/processed in these reactions; this cellular-component assertion does not assign the modifying enzyme, receptor or trafficking activity to collagen.

Summary: Retain the collagen structural class with a verified protein-group detection.

Reason: Original PMID:28344315 S2 row27 and five S3 COL4A5 rows identify human bone-marrow ECM protein. The S3 protein group contains P29400 and P29400-2 and does not resolve their activities separately. Detection is not a tensile measurement: GO:0030020 follows the explicit collagen convention and independent assembly evidence. S2 MGUS nd does not erase the two individual MGUS observations in S3.

Summary: Retain the inherited collagen tensile-strength class.

Reason: Current source identities and exact-term records include experimentally annotated human COL4A1 and worm let-2; these are distinct from the uninspected historical PAINT node. The current term comment permits ECM collagens, and alpha5 network assembly provides target-specific structural grounding. Neither nonfibrillar architecture nor a short donor list refutes this inherited structural class.

Summary: Retain the structural class while qualifying the original proteomic target link.

Reason: The selected PMID:28675934 text describes human tissue ECM extraction and proteomic annotation, but its exact COL4A5 supplementary target row was not recovered. That source-to-target detail remains unverified. Independently verified human alpha5 matrix localization, bone-marrow detection and type-IV assembly support the structural class under the current collagen-term convention; the proteomics is not presented as a force assay.

Summary: Retain extracellular-matrix organization through collagen assembly.

Reason: The alpha5 chain supplies the structural interfaces of type-IV protomers and their terminal-domain network. Actual human alpha5 NC1 self-assembly demonstrates performed assembly work, not merely necessity as an enzyme substrate. This broad process is compatible with nonfibrillar network formation. Current donor records are preserved separately from the uninspected historical PAINT placement.

Summary: The specific collagen-fibril-organization assertion remains unresolved.

Reason: GO:0030199 concerns processes determining collagen-fibril size and arrangement, not a requirement that every participant itself be a fibrillar collagen. The available PMID:29853175 abstract describes fibril assembly generally but does not resolve a COL4A5-specific contribution; bounded original full-text recovery was unsuccessful. Type-IV network identity and the recombinant NC1 assembly evidence in PMID:30443360 neither establish this exact fibril-organizing role nor exclude effects on other collagen fibrils. Retain source-specific uncertainty without converting absent access into evidence against the preserved NAS assertion.

Summary: Retain verified human bone-marrow extracellular-matrix detection.

Reason: Original S2 row27 and five S3 COL4A5 target rows identify the protein in human ECM preparations. The canonical and alternative accessions are grouped, so detection is not isoform-resolved. The differing S2 disease-category classification and individual S3 observations are preserved without inventing universal absence. The protected source cache remains abstract-only; actual original workbook access is recorded separately.

Summary: Retain ECM location with the source-specific table limitation explicit.

Reason: The selected PMID:28675934 main text describes ECM proteomics but the exact alpha5 target supplement was not recovered. Its reference-to-target relationship is UNVERIFIED. Direct human basement-membrane localization and independently verified bone-marrow target detection support retaining the curated ECM location; no new inspection of the missing table is claimed.

Summary: Retain the inherited extracellular-matrix location.

Reason: The exact current source records include positive human COL4A5 proteomic evidence. The target in its own supporting list is legitimate descendant experimental grounding, not circularity. Preserve all source identities and the original qualifier; current literal records and known matrix biology are not misrepresented as a reconstruction of the historical PAINT node.

Summary: Retain the conserved synaptic basement-membrane location.

Reason: The exact mouse Col4a5 donor carries an IDA neuromuscular-junction record from PMID:7885444. Its full text was not recovered and the abstract foregrounds laminin beta2, which does not establish a curation error. Independently read PMID:18817539 mouse Methods, Results and figure captions explicitly examine collagen alpha3–6(IV) in synaptic basal lamina, including alpha5-mutant context and chain-specific staining. This supports the retained ortholog-based location without claiming direct human staining, a new synapse-development process or that all splice products were assayed.

Summary: Recombinant human alpha5 NC1 and synthetic pentastatin bind integrin.

Reason: The actual solid-phase assay coats recombinant human NC1 (reported Gly1461–Thr1685) or pentastatin and adds alpha1beta1 integrin, detected through beta1, with BSA and random-peptide controls. Cellular crosslinked immunoprecipitation corroborates association. This is not binding of isolated beta1 monomer or proof that intact matrix collagen and both full-length products have the same accessible activity. The 20-residue sequence maps to canonical1510–1529 and isoform2 1516–1535; reported peptide coordinates do not establish which whole isoform was assayed. NC1-reactive tissue/ELISA signals do not identify a naturally liberated 20-residue peptide. The current cell-matrix-adhesion child is not required by these binding/barrier assays; no existing annotation or replacement is an ancestor/descendant of this MF. This is retained as a measured fragment activity, without elevating it to a primary core function while the endogenous product and role remain unresolved. The family-level Reactome:R-HSA-2327695 summary mentions type-IV collagen binding and alpha1/alpha2/alpha3 NC1 ligands, but does not independently establish an alpha5-specific intact-chain or released-fragment mechanism.