id: Q68BL7 gene_symbol: OLFML2A product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: OLFML2A (olfactomedin-like protein 2A, photomedin-1) is a secreted, O-glycosylated glycoprotein of 652 residues with an N-terminal signal peptide, cysteine-rich CXCXCX9C motifs, a coiled-coil segment, a Ser/Thr-rich low-complexity linker and a C-terminal olfactomedin (OLF) domain. With its paralog OLFML2B (photomedin-2) it forms a distinct olfactomedin subfamily. The characterized mouse ortholog is secreted as a disulfide-linked homodimer that is proteolytically processed in the middle of the molecule after secretion, and it binds sulfated glycosaminoglycans, preferentially chondroitin sulfate E and heparin, so it is thought to associate with proteoglycan-rich extracellular matrix. It is expressed in retinal photoreceptors (mouse) and, in kidney, by podocytes, where it localizes to the major processes. No catalytic activity, receptor or specific signaling pathway has been established; cancer studies report AP-1-dependent expression and expression-prognosis associations rather than a molecular mechanism. alternative_products: - name: '1' id: Q68BL7-1 - name: '2' id: Q68BL7-2 sequence_note: VSP_029566 - name: '3' id: Q68BL7-3 sequence_note: VSP_029565, VSP_029567 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: action: ACCEPT summary: OLFML2A is a secreted extracellular protein. reason: The PAINT node PTN000573635 is the bilaterian root of the olfactomedin family, and extracellular localization is shared by its experimentally characterized members. OLFML2A sits within that clade (PANTHER PTHR23192:SF29), carries a signal peptide, and its mouse ortholog in the same subfamily was shown experimentally to be secreted. The family-level inference is consistent with the subfamily-specific evidence. supported_by: &id001 - &id004 reference_id: PMID:15836428 supporting_text: 'These proteins, named photomedin-1 and photomedin-2, were secreted as disulphide-bonded dimers (photomedin-1) or oligomers/multimers (photomedin-2) with O-linked carbohydrate chains' - &id002 reference_id: PMID:15836428 supporting_text: 'We screened more than 60000 RIKEN mouse cDNAs for novel ECM (extracellular matrix) proteins' - &id005 reference_id: file:human/OLFML2A/OLFML2A-uniprot.txt record_section: ["DR:Pfam"] supporting_text: 'DR Pfam; PF02191; OLF; 1.' - &id006 reference_id: file:human/OLFML2A/OLFML2A-uniprot.txt record_section: ["FT:SIGNAL"] supporting_text: FT SIGNAL 1..27 - 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: action: ACCEPT summary: OLFML2A is a secreted extracellular protein. reason: The UniProt "Secreted" subcellular location is curated by similarity to mouse Olfml2a (Q8BHP7, same PANTHER subfamily SF29), whose secretion was shown experimentally, and the human protein has a predicted signal peptide. Consistent with the IBA and ISS rows for the same term. supported_by: *id001 - term: id: GO:0005576 label: extracellular region evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in supporting_entities: - UniProtKB:Q8BHP7 review: action: ACCEPT summary: OLFML2A is a secreted extracellular protein. reason: Manual transfer from mouse Olfml2a (Q8BHP7), a one-to-one ortholog in the same PANTHER subfamily (PTHR23192:SF29), which was experimentally shown to be secreted as disulfide-linked dimers. supported_by: *id001 - 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: action: UNDECIDED summary: Family-root IBA for signal transduction; no OLFML2-subfamily evidence for or against it. reason: The IBD was placed at PTN000573635, the bilaterian root of PTHR23192, from three donors, human myocilin (UniProtKB:Q99972) and two mouse genes, one of which (MGI:1202864) also seeds the myocilin-specific node PTN002754680, so the signaling evidence comes from outside the OLFML2 subfamily. OLFML2A is inside the clade that inherits the node, so the inference is formally valid, and there is no evidence of loss in the OLFML2 subfamily. Equally, no experiment on OLFML2A or OLFML2B connects them to a signal transduction mechanism; the only signaling data (AP-1 regulation of OLFML2A expression in breast cancer cells) place OLFML2A downstream of a transcription factor, not as a participant in signal transduction. The PAINT curators placed other myocilin-derived terms (Golgi, osteoblast differentiation) at the myocilin node only, so the root placement of this broad term was deliberate. Without subfamily evidence the claim can be neither confirmed nor refuted for OLFML2A. propagation_review: root_cause: UNRESOLVED failure_modes: [] source_entities: - source_id: PANTHER:PTN000573635 comment: Bilaterian root node of PTHR23192 carrying the signal transduction IBD; OLFML2A (SF29) descends from it. No evidence of loss in the OLFML2 subfamily, but no subfamily-level experimental support either. source_status: UNRESOLVED - source_id: UniProtKB:Q99972 comment: Human myocilin, a donor from a different subfamily; supports the ancestral placement but not specifically OLFML2A. source_status: UNRESOLVED supported_by: - &id003 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:0031012 label: extracellular matrix evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in supporting_entities: - UniProtKB:Q8BHP7 - ensembl:ENSMUSP00000058761 review: action: ACCEPT summary: Photomedin-1 is an ECM-associated extracellular protein. reason: Ensembl Compara transfer from mouse Olfml2a (same PANTHER subfamily SF29), which was identified in a screen for novel ECM proteins with recombinant expression and immunohistochemistry, and which binds proteoglycan glycosaminoglycan chains. ECM association is a reasonable location; it does not imply a structural matrix role. supported_by: - *id002 - *id004 - *id003 - term: id: GO:0042802 label: identical protein binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables supporting_entities: - UniProtKB:Q8BHP7 - ensembl:ENSMUSP00000058761 review: action: KEEP_AS_NON_CORE summary: Photomedin-1 forms disulfide-linked homodimers. reason: Mouse photomedin-1 is secreted as a disulfide-bonded dimer, and UniProt curates human OLFML2A as a homodimer by similarity. This is a real property of the assembly state, transferred within the SF29 subfamily, but it is an architectural feature rather than the protein's principal extracellular binding activity. supported_by: - *id004 - &id007 reference_id: file:human/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: IEA original_reference_id: GO_REF:0000107 qualifier: enables supporting_entities: - UniProtKB:Q8BHP7 - ensembl:ENSMUSP00000058761 review: action: ACCEPT summary: Photomedin-1 binds glycosaminoglycan components of the ECM. reason: Ensembl Compara transfer of the MGI IDA from PMID:15836428 on the SF29 mouse ortholog. Among a panel of ECM components the photomedins bound chondroitin sulfate E and heparin. The glycosaminoglycan terms (heparin binding, chondroitin sulfate binding) are not is_a descendants of extracellular matrix binding, so this term is kept as a correct description and the specific ligands are proposed as separate NEW annotations. supported_by: - *id003 - *id007 - term: id: GO:0035374 label: chondroitin sulfate binding evidence_type: ISS original_reference_id: PMID:15836428 review: action: NEW summary: Binds chondroitin sulfate E, its preferred glycosaminoglycan ligand. reason: Mouse Olfml2a (Q8BHP7, PANTHER SF29 one-to-one ortholog) binds chondroitin sulfate E preferentially among tested ECM components; UniProt curates the human protein accordingly by similarity. This is the most specific ligand-binding activity known for the protein and is more informative than extracellular matrix binding. The OLF domain is conserved, and the human and mouse proteins are in the same subfamily. supported_by: - *id003 - *id007 - term: id: GO:0008201 label: heparin binding evidence_type: ISS original_reference_id: PMID:15836428 review: action: NEW summary: Binds heparin. reason: The same binding panel on the SF29 mouse ortholog showed heparin as the second preferred glycosaminoglycan ligand, and UniProt curates heparin binding for the human protein by similarity to Q8BHP7. supported_by: - *id003 - *id007 references: - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity 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: 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: Mouse photomedin-1 (Olfml2a) is secreted as a disulfide-bonded, O-glycosylated dimer and is proteolytically processed after secretion. supporting_text: 'photomedin-1 was proteolytically processed in the middle of the molecule after secretion' - statement: Photomedins preferentially bind chondroitin sulfate E and heparin among tested ECM components. 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 (Q8BHP7, PANTHER SF29); source of the MGI IDA/IPI annotations transferred to human. Full text (PMC1180717) could not be retrieved on 2026-10-20; the abstract refers to photomedins collectively for glycosaminoglycan binding, while the mouse UniProt entry attributes heparin/CS-E binding to Olfml2a with ECO:0000269 from this paper. - id: PMID:18757743 title: Transcriptome-based systematic identification of extracellular matrix proteins. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Mouse ECM-protein screen; source of the mouse MGI ECM-organization and ECM-location IDA rows. The cached abstract does not name Olfml2a and does not report a positive assembly result for it, so it is not used as support here. - 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. findings: - statement: Olfml2a is expressed exclusively by podocytes in the glomerulus and localizes to podocyte major processes; it is co-expressed with podocyte markers in human glomerular crescents. supporting_text: These proteins were expressed exclusively by podocytes, wherein they localized to major processes reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Expression/localization study (human and rodent kidney) supporting the UniProt tissue-specificity note; establishes where the protein is found, not its molecular function. - id: file:human/OLFML2A/OLFML2A-uniprot.txt title: human/OLFML2A/OLFML2A-uniprot.txt findings: [] core_functions: - description: Secreted, disulfide-linked homodimeric olfactomedin glycoprotein that binds sulfated glycosaminoglycans, preferentially chondroitin sulfate E and heparin, consistent with association with proteoglycan-rich extracellular matrix. Downstream matrix-organizing or signaling consequences are not established. molecular_function: id: GO:0035374 label: chondroitin sulfate binding locations: - id: GO:0031012 label: extracellular matrix supported_by: - *id003 - *id004 - *id007 - *id006 suggested_questions: - question: Does human OLFML2A bind chondroitin sulfate E and heparin with affinities comparable to the mouse protein, and which region (OLF domain or N-terminal cysteine-rich/coiled-coil region) mediates glycosaminoglycan binding? - question: Is the family-root IBA for signal transduction (PTN000573635) justified for the OLFML2 subfamily, given that its donors derive from the myocilin subfamily? suggested_experiments: - description: Quantitative binding (SPR or glycan microarray) of purified human OLFML2A and its post-secretion cleavage fragments to chondroitin sulfate E, heparin and other glycosaminoglycans. - description: Identify native extracellular binding partners of OLFML2A in retina and kidney podocytes by proximity labeling or affinity purification-mass spectrometry.