Cochlin is a secreted extracellular-matrix glycoprotein with an N-terminal LCCL domain and two von Willebrand factor A domains. Its collagen-binding and sulfated-glycan-binding capacities connect it to matrix organization and maintenance, especially in the inner ear. Pathogenic COCH variants can cause dominant progressive audiovestibular disease, while biallelic loss of function also impairs hearing. Proteolytic release of the LCCL region produces a distinct immune-active fragment that can aggregate bacteria and attract immune cells. Cochlin also influences cell shape in cultured human trabecular-meshwork cells.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:21886777 Cochlin induced TREK-1 co-expression and annexin A2 secretio... | KEEP AS NON CORE | Summary: Cochlin associates with annexin A2 in human trabecular-meshwork material. Reason: PMID:21886777 reports reciprocal immunoprecipitation from human trabecular-meshwork extracts with an anti-citrulline control, and an overlay using extract and medium from HA-cochlin-expressing cells. These support the association independently of the overexpression experiments on secretion. A specific adaptor, mechanosensor or channel-regulator activity is not established by the pair. Retain the positive interaction under the campaign policy for supported generic binding. Supporting Evidence: |
| GO:0005518 collagen binding | IDA PMID:22610276 A novel COCH mutation associated with autosomal dominant non... | ACCEPT | Summary: The vWFA2 region of human cochlin binds collagen. Reason: The cited study tests recombinant human vWFA2 preparations by surface plasmon resonance; the F527C variant retains collagen-II binding despite altered stability and aggregation. The earlier PMID:19013156 reports binding of isolated vWFA2 to collagens I, II and IV. Its wild-type affinity is cited by the later paper, not newly measured there. This supports collagen binding, without equating mutant aggregation with loss of binding or extending the domain assay to every splice product. Supporting Evidence: PMID:22610276 the mutant monomeric protein bound to collagen type II |
| GO:0007605 sensory perception of sound | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Conserved cochlin function supports hearing, with an age-dependent mouse loss-of-function phenotype. Reason: The supplied MGI source resolves to mouse Coch/Q62507 and has current same-term experimental grounding in PMID:21073934. Coch-null mice develop high-frequency auditory deficits at advanced age; their phenotype differs from that of G88E knock-in mice. Human recessive loss-of-function evidence independently supports a normal hearing role. Retain the phylogenetic assertion as a physiological consequence of cochlin function, without assigning auditory signal transduction to cochlin. The historical PAINT node placement was not inspected. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002770411 UNRESOLVED Historical PAINT node and MSA not inspected. Current mapped mouse Coch has exact-term experimental evidence; independent human loss-of-function supports the target relationship. |
| GO:0007605 sensory perception of sound | TAS PMID:9806553 Mutations in a novel cochlear gene cause DFNA9, a human nons... | KEEP AS NON CORE | Summary: Human COCH disease genetics support an important hearing role. Reason: The original PMID:9806553 abstract explicitly reports human DFNA9 missense variants in three unrelated kindreds and auditory/vestibular pathology; full text was unavailable. Later human recessive loss-of-function and mouse-null studies independently support the positive hearing relationship. The disease phenotype does not identify cochlin as an auditory receptor or ion channel, so retain the process outside the molecular core. |
| GO:0008360 regulation of cell shape | IMP PMID:21886777 Cochlin induced TREK-1 co-expression and annexin A2 secretio... | KEEP AS NON CORE | Summary: Cochlin changes the shape and protrusions of cultured human trabecular-meshwork cells. Reason: PMID:21886777 tests primary human cells both after cochlin expression and next to methylcellulose pellets releasing purified recombinant cochlin. The latter treatment induces elongated filopodia and movement away from the gradient. Thus the positive cell-shape effect is not based solely on transfection. Its native physiological extent and proposed TREK-1 mechanotransduction route remain less resolved than the measured cell response. Supporting Evidence: PMID:21886777 TM cells developed elongated filopodia |
| GO:0031012 extracellular matrix | IBA GO_REF:0000033 | ACCEPT | Summary: Cochlin is a conserved extracellular-matrix protein. Reason: The supplied current donor identities and same-term records include mouse Coch and human COCH experimental grounding, alongside matrilins and other matrix proteins. Human collagen-domain experiments and the official human matrisome classification independently support the target location. The target in its own source list is valid descendant evidence, not circularity. Current records corroborate biological plausibility; they do not reconstruct the historical PAINT node or alignment. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002544439 UNRESOLVED Historical PAINT node and MSA not inspected. Current donor identities and experimental matrix records, including the human target itself, corroborate this broad location. |
| GO:0031012 extracellular matrix | IDA PMID:22610276 A novel COCH mutation associated with autosomal dominant non... | ACCEPT | Summary: The original human cochlin experiments support extracellular-matrix association. Reason: The cited paper assays secretion of human full-length tagged cochlin and collagen binding by its vWFA2 region. Together with the earlier secretion study and matrisome classification, these support the broad extracellular-matrix location. Intracellular retention of particular disease variants does not negate the normal extracellular role. |
| GO:0031012 extracellular matrix | IEA GO_REF:0000107 | ACCEPT | Summary: The mouse-to-human extracellular-matrix transfer is biologically supported. Reason: The supplied Q62507 identity is mouse Coch, whose current same-term annotation includes experimental evidence. Human cochlin secretion and collagen binding independently support the transferred broad location. Preserve both supplied orthology source identifiers; the historical Ensembl transfer event was not reconstructed. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q62507 · Coch SUPPORTS TRANSFER Official identity is mouse Coch; captured current extracellular-matrix annotations include experimental evidence. Human secretion/binding independently corroborates the target. Historical Ensembl event not inspected. ensembl:ENSMUSP00000128127 UNRESOLVED Original orthology identifier preserved; historical transcript-to-protein transfer was not reconstructed. |
| GO:0140144 non-collagenous component of basement membrane | IEA GO_REF:0000117 | UNDECIDED | Summary: The precise non-collagenous basement-membrane compartment remains unresolved. Reason: GO:0140144 specifies the solid non-collagenous compartment of basement membrane. Cochlin collagen-IV binding, basilar-membrane staining and supporting-cell staining along a basement membrane do not individually establish that precise residence. The current ARBA00096893 conditions do not match the captured COCH domain/FunFam record, but that does not demonstrate what the historical rule matched. Preserve the source assertion and the positive broad matrix evidence while leaving this narrower assignment unresolved. Propagation Review Root cause: UNRESOLVED Sources checked: ARBA:ARBA00096893 UNRESOLVED Current authentic rule condition sets and target domain/FunFam record are captured; none matches. Historical rule state and exact compartment evidence remain unresolved, so no historical mapping-error claim is made. |
| GO:0140149 non-collagenous component of interstitial matrix | TAS PMID:36399478 MatrisomeDB 2.0: 2023 updates to the ECM-protein knowledge d... | UNDECIDED | Summary: Broad matrisome classification is verified; the narrower interstitial-matrix source link is unresolved. Reason: The official human matrisome masterlist contains COCH/O43405 as an ECM glycoprotein. The PMID:36399478 database paper explains its proteomic integration, but the exact target record and interstitial-compartment attribution could not be inspected. Mouse tendon proteomics and physiological changes support a matrix-associated role without directly resolving the solid interstitial compartment. Retain the original TAS assertion for resolution rather than deny its broader matrix biology. Other genes' accepted database annotations do not resolve this target-specific compartment link. Basement-membrane and interstitial residence are tissue-dependent possibilities, not mutually exclusive gene-level alternatives. |
| GO:0042056 chemoattractant activity | IDA PMID:30905438 Cleaved Cochlin Sequesters Pseudomonas aeruginosa and Activa... | NEW | Summary: Human recombinant LCCL promotes mouse neutrophil migration toward the lower Transwell chamber. Reason: Original Figure 7E and STAR Methods compare isolated mouse marrow neutrophils migrating into a lower chamber containing purified human LCCL with a no-LCCL control (five replicates per condition). The key-resource table distinguishes this reagent from the full-length processing construct. This controlled asymmetric exposure supports assay-scoped chemoattractant activity beyond infection rescue alone. A checkerboard assay was not reported: a chemokinetic contribution or responder-derived relay is not excluded, and receptor-dependent directional sensing is not established. PMID:23684986 instead links reduced MCP-1/KC secretion to later recruitment defects in infected mouse lung; that indirect route is immune context, not the direct assay supporting this MF. No exact natural isoform or all-product activity is inferred. The axon-guidance-specific child does not fit and typed coverage remains nonredundant. Supporting Evidence: PMID:30905438 recruits resident immune cells file:human/COCH/COCH-primary-excerpts.md |
| GO:0008201 heparin binding | IDA PMID:35901072 Involvement of cochlin binding to sulfated heparan sulfate/h... | NEW | Summary: A human cochlin reporter construct recognizes heparin with sulfation-dependent specificity. Reason: The original Methods describe a sequence-checked human cochlin clone carrying a reported natural T-to-S variant, fused to CD8alpha/CD3zeta in a cell-surface reporter. Heparin induces the reporter, whereas N-desulfation reduces the response; expression controls and a CD8alpha/CD3zeta construct lacking the cochlin moiety are reported. The human cochlin moiety, rather than the reporter tags alone, is therefore the supported binding determinant in this assay; no native receptor activity is assigned. Independent purified mouse cochlin-Fc/Protein-A assays corroborate binding but are not relabeled as human experiments. Later mouse domain-deletion data require vWA1 and do not support assigning this activity to isolated LCCL. This is a supported secondary matrix-binding capability, not a new process or an assertion that every natural product has identical specificity. |
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Download this section (compressed HTML)Q: Which natural cochlin cleavage products and receptors account for neutrophil attraction, and how do they differ from the intact matrix-associated protein?
Q: Does the C-terminal replacement in O43405-2 alter secretion, collagen binding or glycan specificity despite retaining the LCCL sequence?
Q: What direct interaction or physical mechanism connects cochlin to tendon fibril organization, and which tissues place it within a basement-membrane versus interstitial solid matrix?
Experiment: Compare sequence-verified canonical and alternative full-length human products, purified collagen-binding domains and native cleavage products in matched secretion, collagen and glycan-binding assays.
Hypothesis: The altered vWFA2 tail changes matrix engagement without necessarily abolishing all LCCL-associated activities.
Experiment: Use purified sequence-defined human LCCL with checkerboard Transwell gradients and receptor perturbations in human neutrophils, controlling viability and general motility.
Hypothesis: The increased migration in the lower-chamber assay contains a gradient-dependent component separable from chemokinesis or responder-derived chemokine signaling.
Experiment: Localize endogenous cochlin by immunogold microscopy against basement-membrane and interstitial-matrix markers, with validated antibody and tissue controls.
Hypothesis: Cochlin occupies tissue-specific matrix compartments that broad matrisome classification cannot resolve.
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