OLFML2A

UniProt ID: A0A9L0SKW1
Organism: Equus caballus
Review Status: COMPLETE
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Gene Description

OLFML2A (olfactomedin-like protein 2A, photomedin-1) is a member of the olfactomedin-domain glycoprotein family, in the OLFML2A subfamily of the olfactomedin-related proteins. It has an N-terminal region carrying tandem CXCXCX9C cysteine motifs, a central coiled-coil and disordered segment, and a C-terminal olfactomedin domain. In mammals the canonical product has an N-terminal signal peptide. In the mouse it is secreted as a disulfide-linked, O-glycosylated homodimer, cleaved in the middle of the molecule after secretion, and it binds the sulfated glycosaminoglycans chondroitin sulfate E and heparin. Photomedin-1 is found in the outer segments of retinal photoreceptors and in the major processes of kidney podocytes. Its physiological role beyond glycosaminoglycan binding is not known. The horse locus encodes a signal-peptide-bearing product that is nearly identical in length to the human protein. This UniProt entry (599 residues) is one of several shorter alternative models of the gene. It lacks the signal peptide and a 22-residue N-terminal segment, but it keeps the complete olfactomedin domain.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005576 extracellular region
IEA
GO_REF:0000044 		ACCEPT
Summary: OLFML2A is a secreted extracellular protein. The horse locus encodes a leader-bearing form, although this particular leaderless model would not be secreted on its own.
Reason: At the gene level the extracellular location is well grounded. (1) A0A9L0SKW1 belongs to PANTHER subfamily PTHR23192:SF29 (OLFACTOMEDIN-LIKE PROTEIN 2A), with experimentally characterized mouse photomedin-1 (Q8BHP7). That protein is secreted as a disulfide-bonded dimer and is proteolytically processed after secretion (PMID:15836428). (2) PAINT places extracellular region at the family root node PTN000573635. All SF29 members descend from that node, and human OLFML2A carries the corresponding IBA. (3) The earlier review left this row UNDECIDED pending a check of the horse transcript models. That check is now done. The same Ensembl gene (ENSECAG00000023908) has a RefSeq isoform, XP_023484611.2 (650 aa), which carries a hydrophobic leader homologous to the human 1-27 signal peptide and pairs with human over all but five positions. A0A9L0SKW1 is one of several leaderless alternative models of the locus, comparable to human isoform 2, which lacks residues 1-39. On its own sequence it has no secretion signal, and the UniProt mapping behind this row is an ARBA family rule rather than a sequence feature. GO describes the gene product, though, and the gene product is secreted. The row is accepted, and the identity caveat is recorded in the notes.
Supporting Evidence:
PMID:15836428
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, although photomedin-1 was proteolytically processed in the middle of the molecule after secretion.
file:HORSE/OLFML2A/OLFML2A-bioinformatics/RESULTS-rereview.md
The horse locus encodes a leader-bearing product.
file:HORSE/OLFML2A/OLFML2A-bioinformatics/RESULTS-rereview.md
The benchmark accession A0A9L0SKW1 is one of several leaderless alternative models of the same gene.
file:HORSE/OLFML2A/OLFML2A-uniprot.txt
DR PANTHER; PTHR23192:SF29; OLFACTOMEDIN-LIKE PROTEIN 2A; 1.
file:human/OLFML2A/OLFML2A-uniprot.txt
FT SIGNAL 1..27
GO:0050840 extracellular matrix binding
ISS
PMID:15836428
Identification and characterization of photomedins: novel ol... 		NEW
Summary: Binding of sulfated glycosaminoglycans, transferred within the OLFML2A subfamily from mouse photomedin-1.
Reason: Mouse photomedin-1 (Q8BHP7) carries an IDA annotation for this term from PMID:15836428. In a panel of ECM components it bound chondroitin sulfate E and heparin preferentially. The horse protein is a PANTHER SF29 ortholog of the mouse protein, and its olfactomedin domain is intact, including the cysteines of the conserved intradomain disulfide. Only the mouse protein has been assayed, and the binding site has not been mapped, so the transfer is made at the level of the mouse IDA term. More specific heparin-binding or chondroitin-sulfate-binding terms are not used. This is the only molecular activity established for the subfamily. It is not evidence that the protein organizes the matrix.
Supporting Evidence:
PMID:15836428
Among a panel of ECM components, including glycosaminoglycans, photomedins preferentially bound to chondroitin sulphate-E and heparin.
file:HORSE/OLFML2A/OLFML2A-uniprot.txt
DR PANTHER; PTHR23192:SF29; OLFACTOMEDIN-LIKE PROTEIN 2A; 1.
file:human/OLFML2A/OLFML2A-uniprot.txt
SUBUNIT: Homodimer. Binds to heparin and chondroitin sulfate E.

Core Functions

Secreted olfactomedin-domain glycoprotein that binds the sulfated glycosaminoglycans chondroitin sulfate E and heparin in the extracellular space. This activity is inferred for horse from the mouse ortholog in PANTHER subfamily SF29 and applies to the leader-bearing product of the locus. The physiological consequence of the binding is unknown.

Molecular Function:
extracellular matrix binding
Cellular Locations:
extracellular region
Supporting Evidence:
  • PMID:15836428
    Among a panel of ECM components, including glycosaminoglycans, photomedins preferentially bound to chondroitin sulphate-E and heparin.
  • file:HORSE/OLFML2A/OLFML2A-bioinformatics/RESULTS-rereview.md
    The horse locus encodes a leader-bearing product.

References

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Suggested Questions for Experts

Q: Are the leaderless horse OLFML2A transcripts (A0A9L0SKW1, A0A3Q2LAT7, RefSeq X2-X4) translated, and if so, where do their products go? RefSeq X1 shows that the locus encodes a signal-peptide-bearing product. The leaderless models begin at a different N-terminus (MDSQ-VFGD) in place of the leader.

Q: Is the 22-residue segment opposite human residues 123-144, which only the A0A9L0SKW1 model lacks, an alternatively spliced exon? Does its loss affect the N-terminal cysteine-motif region or dimerization?

Q: Is the equine protein, like human and mouse photomedin-1, cleaved after secretion and deposited in a defined tissue compartment - and is the equine kidney expression podocyte-restricted as in human?

Q: Is the PAINT signal-transduction assertion at the olfactomedin family root (PTN000573635) meant to apply to OLFML2A? It has no OLFML2A-specific support, and horse A0A9L0SKW1 does not carry that IBA.

Suggested Experiments

Experiment: 5-prime RACE and long-read sequencing of OLFML2A transcripts from horse retina and kidney to establish the true translation start and internal exon structure, together with ribosome profiling or targeted proteomics to test which N-terminus is translated.

Hypothesis: The equine OLFML2A locus mainly produces the signal-peptide-bearing transcript (RefSeq XP_023484611.2), and leaderless models such as A0A9L0SKW1 are minor or untranslated alternative products.

Type: transcript 5-prime mapping / gene-model validation

Experiment: Express tagged versions of the selected 599-residue sequence and of any transcript-verified signal-peptide-bearing form in a mammalian cell line; assay medium versus lysate by western blot for secretion, non-reducing versus reducing SDS-PAGE for disulfide-linked dimers, and glycosaminoglycan affinity chromatography against a panel including chondroitin sulfate E and heparin, with human OLFML2A as the positive control.

Hypothesis: Whichever equine form is real, it enters the secretory pathway and is released as a disulfide-bonded dimer that binds chondroitin sulfate E and heparin.

Type: secretion and glycosaminoglycan-binding assay

Experiment: Immunohistochemistry and immunoelectron microscopy on horse retina and kidney sections using an antibody raised against the conserved olfactomedin domain, with colocalization against vimentin in podocytes as in the human study.

Hypothesis: Equine OLFML2A occupies the same tissue niches as the human protein - photoreceptor outer segment and podocyte major processes.

Type: tissue immunolocalization

External Prediction Reviews

These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.

ProtNLM2 External predictions

View prediction review YAML · OLFML2A-protnlm-predictions-review.yaml · Review status: COMPLETE

A0A9L0SKW1 is a leaderless alternative model of the horse OLFML2A (photomedin-1) locus. Compared with the canonical signal-peptide-bearing product (RefSeq XP_023484611.2, counterpart of human Q68BL7 isoform 1), it lacks the N-terminal signal peptide (human residues 1-27) and a 22-residue segment opposite human 123-144, but keeps the complete olfactomedin domain, its conserved disulfide cysteines and the region matching the human coiled coil. The protein belongs to PANTHER subfamily PTHR23192:SF29 with experimentally characterized mouse photomedin-1, and the only horse GOA annotation is extracellular region. Scored for this sequence, extracellular matrix and extracellular matrix binding require secretion, which this product cannot achieve without a leader, so they are incorrect for this accession although true of the gene. Extracellular matrix organization is uncertain, because how the gene takes part in that process is not established. Identical protein binding is uncertain: the characterized dimer is disulfide-linked and so formed in the secretory pathway, and whether the leaderless product self-associates by other means is unknown.

Source documents: projects/PROTNLM_EVALUATION/mammal-benchmark/horse40-predictions.csv · projects/PROTNLM_EVALUATION/mammal-benchmark/predictions.jsonl.gz · projects/PROTNLM_EVALUATION/mammal-benchmark/paired-sequences/OLFML2A.json · genes/HORSE/OLFML2A/OLFML2A-hypotheses/horse40-extracellular-matrix-localization/openscientist.md · genes/HORSE/OLFML2A/OLFML2A-ai-review.yaml · genes/human/OLFML2A/OLFML2A-ai-review.yaml

Review score: 2 = concordant with evidence; 1 = uncertain; 0 = discordant with evidence. This is an assessment score, not a model probability.

GO:0030198 extracellular matrix organization GO_BP
UNC — Uncertain Review score: 1/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08
Review rationale: A0A9L0SKW1 lacks the N-terminal signal peptide: its N-terminus MDSQ-VFGD replaces the hydrophobic leader that aligns with human signal peptide 1-27 (maximum Kyte-Doolittle hydropathy 0.25 versus 2.93 for human and 3.13 for the leader-bearing horse isoform X1), and the record carries no SIGNAL or transmembrane feature; its Secreted annotation comes from an ARBA family rule. The product therefore lacks the route by which photomedin-1 reaches the matrix. That does not refute the process term, because the mechanism by which OLFML2A takes part in extracellular matrix organization has not been established: mouse photomedin-1 is a matrix-associated glycosaminoglycan-binding protein, and the Manabe et al. ECM screen behind the mouse acts_upstream_of_or_within annotation assayed several properties (ECM assembly, interactions with ECM molecules, glycosaminoglycan modification, cell adhesion) without the cached abstract saying which one Olfml2a satisfied. With the participation mechanism unknown, a contribution by the leaderless product through some other route is neither shown nor excluded, and the gene-level support for the term is itself weak, so the prediction can be neither confirmed nor refuted for this accession.
Supporting Evidence:
GO:0042802 identical protein binding GO_MF
UNC — Uncertain Review score: 1/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08
Review rationale: Horse GOA carries no molecular-function annotation, so the term would be novel for the gene. The experimental basis is mouse photomedin-1, secreted as a disulfide-bonded dimer, and curated human UniProt records OLFML2A as a homodimer by similarity. That disulfide-linked dimer forms in the oxidizing secretory pathway, which A0A9L0SKW1 cannot enter because it lacks the N-terminal signal peptide (its N-terminus MDSQ-VFGD replaces the leader matching human 1-27). The accession also lacks the 22-residue segment opposite human 123-144, but retains the region matching the human coiled coil (157-183) and the olfactomedin domain. Which region mediates photomedin-1 self-association, and whether a cytosolic leaderless product could dimerize non-covalently, is unresolved, so the prediction can be neither confirmed nor refuted for this product.
Supporting Evidence:
GO:0031012 extracellular matrix GO_CC
NPI — Nonparalog incorrect Review score: 0/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08
DOMAIN ARCHITECTURE MISMATCH
Review rationale: The term is true of the OLFML2A gene: mouse photomedin-1, the characterized member of PANTHER subfamily SF29, was identified in a screen for novel ECM proteins, is secreted, and binds chondroitin sulfate E and heparin, and the horse locus encodes a leader-bearing product. It is not correct for the sequence ProtNLM2 was given. A0A9L0SKW1 lacks the N-terminal signal peptide: its N-terminus MDSQ-VFGD replaces the hydrophobic leader that aligns with human signal peptide 1-27 (maximum hydropathy 0.25 versus 2.93 for human and 3.13 for the leader-bearing horse isoform X1), and the record carries no SIGNAL or transmembrane feature; its Secreted annotation comes from an ARBA family rule. Without a signal peptide this product has no route into the secretory pathway and cannot be deposited in extracellular matrix. Novelty against horse GOA (extracellular region only) is not at issue; the prediction fails on product architecture.
Supporting Evidence:
GO:0050840 extracellular matrix binding GO_MF
NPI — Nonparalog incorrect Review score: 0/2
Prediction method: ProtNLM2 · Version: UniProt API snapshot 2026-09-08
DOMAIN ARCHITECTURE MISMATCH
Review rationale: Mouse photomedin-1 bound chondroitin sulfate E and heparin preferentially among a panel of ECM components, and the horse gene review assigns this activity to the gene by sequence similarity. The olfactomedin domain is intact in A0A9L0SKW1, but the binding partners are extracellular glycosaminoglycans that the protein can only reach after secretion. A0A9L0SKW1 lacks the N-terminal signal peptide: its N-terminus MDSQ-VFGD replaces the hydrophobic leader that aligns with human signal peptide 1-27 (maximum hydropathy 0.25 versus 2.93 for human and 3.13 for the leader-bearing horse isoform X1), and the record carries no SIGNAL or transmembrane feature; its Secreted annotation comes from an ARBA family rule. The leaderless product therefore cannot carry out extracellular matrix binding; the activity belongs to the leader-bearing product of the locus.
Supporting Evidence:

Deep Research

Cyberian

(OLFML2A-deep-research-cyberian.md)

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OpenScientist

(OLFML2A-hypotheses/horse40-extracellular-matrix-localization/openscientist.md)

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📚 Additional Documentation

Notes

(OLFML2A-notes.md)

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Bioinformatics Results

(RESULTS.md)

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📄 View Raw YAML

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