id: Q8BHP7 gene_symbol: Olfml2a product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:10090 label: Mus musculus description: Olfml2a (olfactomedin-like protein 2A, photomedin-1) is a secreted, O-glycosylated glycoprotein of 681 residues with an N-terminal signal peptide (1-32), cysteine-rich CXCXCX9C motifs, a coiled-coil segment, a long low-complexity, Pro-rich linker and a C-terminal olfactomedin (OLF) domain (423-681). With its paralog Olfml2b (photomedin-2) it forms a distinct subfamily of the olfactomedin family. The protein is secreted as a disulfide-bonded homodimer that is not N-glycosylated but carries O-linked glycans, and it is cleaved in the middle of the molecule (near Lys-301) after secretion. Among a panel of extracellular matrix components it binds sulfated glycosaminoglycans, preferentially chondroitin sulfate E and heparin, and it is deposited in extracellular matrix in tissues. It is expressed in lung, eye, testis, uterus and ovary; in the retina it is restricted to the photoreceptor outer-segment layer, and it has also been reported in the major processes of kidney podocytes. No catalytic activity, cell-surface receptor or signaling pathway has been identified, and its physiological role remains unknown. existing_annotations: - term: id: GO:0005576 label: extracellular region evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in supporting_entities: - MGI:MGI:1202864 - MGI:MGI:1860437 - MGI:MGI:2387329 - MGI:MGI:2388361 - MGI:MGI:2443310 - MGI:MGI:2444741 - MGI:MGI:2685142 - PANTHER:PTN000573635 - RGD:727879 - UniProtKB:O95897 - UniProtKB:Q6UX06 - UniProtKB:Q99972 - UniProtKB:Q9IAK4 - UniProtKB:Q9XTA3 review: summary: Olfml2a is a secreted protein; extracellular region is correct, inherited from the PTHR23192 root node and directly supported in this species. action: ACCEPT reason: The IBD sits at PTN000573635, the root of the olfactomedin family, and is seeded by many secreted family members. Olfml2a (PTHR23192:SF29) descends from that node and has its own experimental support for secretion (signal peptide confirmed by N-terminal sequencing; secreted dimer in culture medium), so MGI:2444741 legitimately appears among the donors. Extracellular region is accepted; the more specific extracellular matrix location is also accepted from the IDA rows. supported_by: - reference_id: PMID:15836428 supporting_text: were secreted as disulphide-bonded dimers (photomedin-1) or oligomers/multimers (photomedin-2) with O-linked carbohydrate chains - reference_id: file:mouse/Olfml2a/Olfml2a-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: 'CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:15836428}.' - term: id: GO:0005576 label: extracellular region evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0243 review: summary: UniProt SubCell mapping of the experimentally curated 'Secreted' location to extracellular region. action: ACCEPT reason: The mapping source is a UniProt subcellular location statement backed by experimental evidence (ECO:0000269, PMID:15836428). Consistent with the IBA row for the same term. supported_by: - reference_id: file:mouse/Olfml2a/Olfml2a-uniprot.txt record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: 'CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:15836428}.' - term: id: GO:0007165 label: signal transduction evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in supporting_entities: - MGI:MGI:1202864 - MGI:MGI:1860437 - PANTHER:PTN000573635 - UniProtKB:Q99972 review: summary: Family-root IBA for signal transduction, seeded from outside the OLFML2 subfamily; no Olfml2a or Olfml2b experiment addresses signaling. action: UNDECIDED reason: The IBD was placed at PTN000573635, the bilaterian root of PTHR23192, from three donors (human myocilin UniProtKB:Q99972 and two mouse genes, MGI:1202864 and MGI:1860437), none in the OLFML2 subfamily, and Olfml2a itself is not among the donors for this term. Olfml2a descends from the node and there is no evidence of loss in SF29, so the inference is formally valid, but no experiment on Olfml2a identifies a receptor, a signaling partner or a downstream pathway; its only established activities are glycosaminoglycan binding and matrix deposition. PAINT curators kept other myocilin-derived terms at the myocilin-specific node, so the root placement was a deliberate choice that this review neither confirms nor refutes. Kept UNDECIDED, consistent with the human OLFML2A review. supported_by: - reference_id: PMID:15836428 supporting_text: These results, together, indicate that photomedins are novel olfactomedin-domain-containing extracellular proteins capable of binding to proteoglycans containing these glycosaminoglycan chains. propagation_review: root_cause: UNRESOLVED failure_modes: [] source_entities: - source_id: PANTHER:PTN000573635 source_status: UNRESOLVED comment: Root node of PTHR23192 carrying the signal transduction IBD; Olfml2a (SF29) descends from it, but the experimental donors lie outside the OLFML2 subfamily and no subfamily member has signaling evidence. - term: id: GO:0030198 label: extracellular matrix organization evidence_type: IDA original_reference_id: PMID:18757743 qualifier: acts_upstream_of_or_within review: summary: Experimental MGI annotation from a systematic ECM-protein screen; the specific Olfml2a result behind it is not visible in the cached abstract. action: UNDECIDED reason: PMID:18757743 screened candidate secreted proteins for several activities, including ECM-assembling activity, ECM interactions, glycosaminoglycan modification and cell adhesion, and identified 16 ECM proteins. The cached record is abstract-only and the PNAS full text could not be retrieved (PMC XML download blocked by the publisher), so it cannot be checked whether Olfml2a scored positive in the matrix-assembly assay or was annotated on the basis of matrix deposition alone. The curator saw the full text and used the weak acts_upstream_of_or_within qualifier, so the row is not removed; but being deposited in matrix and binding glycosaminoglycans does not by itself show that the protein organizes matrix. PAINT did not propagate this term from Olfml2a to SF29 relatives, and the PTHR23192 family review rates its scope UNRESOLVED. supported_by: - reference_id: PMID:18757743 supporting_text: These assays screened the candidate proteins for ECM-assembling activities, interactions with other ECM molecules, modifications with glycosaminoglycans, and cell-adhesive activities - term: id: GO:0031012 label: extracellular matrix evidence_type: IDA original_reference_id: PMID:15836428 qualifier: located_in review: summary: Photomedin-1 was identified in an ECM-protein screen and localized by immunohistochemistry as an extracellular, proteoglycan-binding protein. action: ACCEPT reason: The paper identified photomedins by screening for novel ECM proteins followed by recombinant expression and immunohistochemistry, and showed binding to proteoglycan-associated glycosaminoglycans. Matrix association is the most specific location supported for this secreted protein. supported_by: - reference_id: PMID:15836428 supporting_text: We screened more than 60000 RIKEN mouse cDNAs for novel ECM (extracellular matrix) proteins by extensive computational screening followed by recombinant expression and immunohistochemical characterization. - term: id: GO:0031012 label: extracellular matrix evidence_type: IDA original_reference_id: PMID:18757743 qualifier: located_in review: summary: Systematic immunohistochemistry-based ECM screen including Olfml2a supports extracellular matrix localization. action: ACCEPT reason: The screen combined in vitro assays with immunohistochemistry to define ECM proteins; extracellular matrix localization is consistent with the independent photomedin study and with secretion of the protein. supported_by: - reference_id: PMID:18757743 supporting_text: We identified 16 ECM proteins, of which seven were localized in basement membrane (BM) zones. - term: id: GO:0042802 label: identical protein binding evidence_type: IPI original_reference_id: PMID:15836428 qualifier: enables supporting_entities: - PR:Q8BHP7 review: summary: Olfml2a is secreted as a disulfide-bonded homodimer. action: MODIFY reason: The self-interaction is specifically homodimerization (disulfide-bonded dimers, UniProt 'Homodimer' with experimental evidence), so protein homodimerization activity (GO:0042803, an is_a descendant of identical protein binding) is the more precise term. Dimerization is a structural property rather than the protein's core function. proposed_replacement_terms: - id: GO:0042803 label: protein homodimerization activity supported_by: - reference_id: PMID:15836428 supporting_text: were secreted as disulphide-bonded dimers (photomedin-1) - reference_id: file:mouse/Olfml2a/Olfml2a-uniprot.txt record_section: ["CC:SUBUNIT"] supporting_text: 'CC -!- SUBUNIT: Homodimer. Binds to heparin and chondroitin sulfate E.' - term: id: GO:0050840 label: extracellular matrix binding evidence_type: IDA original_reference_id: PMID:15836428 qualifier: enables review: summary: Binds ECM components, preferentially the glycosaminoglycans chondroitin sulfate E and heparin. action: ACCEPT reason: Direct binding assays against a panel of ECM components including glycosaminoglycans. The ligand-specific terms chondroitin sulfate binding and heparin binding are not is_a descendants of extracellular matrix binding, so they are added as NEW rows alongside this accepted term rather than as a MODIFY. supported_by: - reference_id: PMID:15836428 supporting_text: Among a panel of ECM components, including glycosaminoglycans, photomedins preferentially bound to chondroitin sulphate-E and heparin. - term: id: GO:0035374 label: chondroitin sulfate binding evidence_type: IDA original_reference_id: PMID:15836428 review: summary: Binds chondroitin sulfate E, its preferred glycosaminoglycan ligand. action: NEW reason: The same binding experiments that support the existing ECM-binding IDA show chondroitin sulfate E as the preferred ligand, and UniProt curates this binding for the mouse protein with experimental evidence from PMID:15836428. This is the most specific activity known for Olfml2a and is the one to use as the reference for transfer to SF29 orthologs (the human OLFML2A review already carries it by ISS). supported_by: - reference_id: PMID:15836428 supporting_text: Among a panel of ECM components, including glycosaminoglycans, photomedins preferentially bound to chondroitin sulphate-E and heparin. - reference_id: file:mouse/Olfml2a/Olfml2a-uniprot.txt record_section: ["CC:SUBUNIT"] supporting_text: 'CC -!- SUBUNIT: Homodimer. Binds to heparin and chondroitin sulfate E.' - term: id: GO:0008201 label: heparin binding evidence_type: IDA original_reference_id: PMID:15836428 review: summary: Binds heparin. action: NEW reason: Heparin was the second preferred glycosaminoglycan ligand in the same binding panel; UniProt records heparin binding for the mouse protein with experimental evidence. supported_by: - reference_id: PMID:15836428 supporting_text: photomedins preferentially bound to chondroitin sulphate-E and heparin - reference_id: file:mouse/Olfml2a/Olfml2a-uniprot.txt record_section: ["CC:SUBUNIT"] supporting_text: 'CC -!- SUBUNIT: Homodimer. Binds to heparin and chondroitin sulfate E.' references: - 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: PMID:15836428 title: 'Identification and characterization of photomedins: novel olfactomedin-domain-containing proteins with chondroitin sulphate-E-binding activity.' full_text_unavailable: true findings: - statement: Photomedin-1 (Olfml2a) is secreted as a disulfide-bonded, O-glycosylated dimer and is proteolytically processed mid-molecule after secretion. supporting_text: were secreted as disulphide-bonded dimers (photomedin-1) or oligomers/multimers (photomedin-2) with O-linked carbohydrate chains, although photomedin-1 was proteolytically processed in the middle of the molecule after secretion - statement: In retina, photomedin-1 is restricted to photoreceptor outer segments. supporting_text: In the retina, photomedin-1 was selectively expressed in the outer segment of photoreceptor cells - statement: Photomedins preferentially bind chondroitin sulfate E and heparin. supporting_text: photomedins preferentially bound to chondroitin sulphate-E and heparin reference_review: relevance: HIGH correctness: VERIFIED review_notes: Primary characterization of mouse photomedin-1/Olfml2a (PubMed-verified, Biochem J 2005). Abstract-only in cache; PMC full-text XML not retrievable. Source of all experimental Olfml2a annotations except the ECM-organization row. - id: PMID:18757743 title: Transcriptome-based systematic identification of extracellular matrix proteins. full_text_unavailable: true findings: - statement: Systematic screen of secreted mouse proteins for ECM-assembling activity, ECM interactions, GAG modification and cell adhesion, identifying 16 ECM proteins. supporting_text: We identified 16 ECM proteins, of which seven were localized in basement membrane (BM) zones. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified (PNAS 2008). Abstract does not name Olfml2a; the Olfml2a-specific result behind the MGI ECM and ECM-organization rows is in the full text, which the publisher blocks from PMC XML download. - id: PMID:22913984 title: Neuronal proteins are novel components of podocyte major processes and their expression in glomerular crescents supports their role in crescent formation. full_text_unavailable: true findings: - statement: Olfml2a is expressed by podocytes and localizes to podocyte major processes; it is also found in glomerular crescents of human kidneys. supporting_text: These proteins were expressed exclusively by podocytes, wherein they localized to major processes reference_review: relevance: LOW correctness: VERIFIED review_notes: Expression/localization study; the abstract does not state the species used for the major-process localization (human for the crescent immunohistochemistry). Used for description only, not for an annotation. - id: file:mouse/Olfml2a/Olfml2a-uniprot.txt title: UniProtKB/Swiss-Prot entry Q8BHP7 (OLM2A_MOUSE) findings: - statement: PANTHER subfamily PTHR23192:SF29, the same subfamily as human OLFML2A. record_section: ["DR:PANTHER"] supporting_text: 'DR PANTHER; PTHR23192:SF29; OLFACTOMEDIN-LIKE PROTEIN 2A; 1.' core_functions: - description: Secreted, disulfide-linked homodimeric olfactomedin-domain glycoprotein that binds sulfated glycosaminoglycans, preferentially chondroitin sulfate E and heparin, and is deposited in extracellular matrix, consistent with association with chondroitin-sulfate/heparan-sulfate proteoglycans. These binding activities are experimentally established in mouse; any downstream matrix-organizing or signaling role is not. molecular_function: id: GO:0035374 label: chondroitin sulfate binding locations: - id: GO:0031012 label: extracellular matrix supported_by: - reference_id: PMID:15836428 supporting_text: Among a panel of ECM components, including glycosaminoglycans, photomedins preferentially bound to chondroitin sulphate-E and heparin. - reference_id: PMID:15836428 supporting_text: were secreted as disulphide-bonded dimers (photomedin-1) suggested_questions: - question: Which region of Olfml2a (the N-terminal cysteine-rich/coiled-coil half or the C-terminal OLF domain released by the post-secretion cleavage) carries the chondroitin sulfate E and heparin binding? - question: Did Olfml2a score positive for ECM-assembling activity in the Manabe et al. 2008 screen, and should extracellular matrix organization be extended to the OLFML2 subfamily? - question: Is the photoreceptor outer-segment signal of Olfml2a in the interphotoreceptor matrix, and which proteoglycan carries its chondroitin sulfate E ligand there? suggested_experiments: - description: Quantitative binding (SPR or glycan microarray) of full-length Olfml2a and its N- and C-terminal cleavage fragments to chondroitin sulfate E, heparin/heparan sulfate and other glycosaminoglycans. - description: Characterize retinal and podocyte phenotypes of Olfml2a knockout mice (photoreceptor outer-segment structure, interphotoreceptor matrix composition, podocyte process morphology).