GLIPR1L2 is an isoform-rich, testis-enriched member of the mammalian GLIPR1/CAP protein family. The 344-amino-acid canonical protein contains an SCP/CAP domain, a predicted single transmembrane helix, and a long acidic, disordered C-terminal region; alternative splicing produces six named UniProt isoforms with substantially different termini. GLIPR1L2 transcription is p53 responsive and is detected in several tissues, with highest expression in testis. A deletion spanning the three neighboring mouse Glipr1-like genes did not impair natural fecundity, reproductive-tract histology, sperm morphology, or sperm motility. GLIPR1L2's direct molecular activity, native physiological complex, membrane topology, and biological role remain unknown.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005576 extracellular region | IBA GO_REF:0000033 | UNDECIDED | Summary: PAINT transfers active extracellular-region localization from a broad set of CAP-family sources. GLIPR1L2 has a CAP domain and predicted single-pass membrane architecture, but its topology and extracellular activity have not been measured directly. Reason: An extracellular or luminal N-terminal CAP domain is structurally plausible, but the reviewed record does not specify membrane orientation or a cleaved signal peptide, and the abstract-only human discovery paper does not report protein localization. The qualifier is_active_in additionally presupposes an activity that remains unknown. The annotation should not be rejected solely because direct evidence is missing, but it cannot yet be confidently accepted. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000036124 · broad PTHR10334 ancestral node UNRESOLVED Multiple secreted and membrane CAP-family sources support an ancestral extracellular context, but target isoform topology and activity are unresolved. Supporting Evidence: file:human/GLIPR1L2/GLIPR1L2-uniprot.txt FT TRANSMEM 254..274 file:human/GLIPR1L2/GLIPR1L2-notes.md Leave `extracellular region` (IBA) undecided. file:human/GLIPR1L2/GLIPR1L2-deep-research-manual.md The family-level extracellular IBA should therefore remain undecided pending direct evidence. |
| GO:0060090 molecular adaptor activity | IBA GO_REF:0000033 | REMOVE | Summary: The PAINT annotation is seeded only by mouse Glipr1l1, whose nonenzymatic sperm role is supported by an IZUMO1-containing complex and effects on IZUMO1 redistribution during the acrosome reaction. Reason: GLIPR1L2 is a distinct, divergent CAP-family paralog. No GLIPR1L2 experiment establishes an IZUMO1 complex, acrosomal localization, partner-bridging activity, or any other native adaptor mechanism. Family membership, testis enrichment, and high-throughput binary interactions are insufficient to transfer the specialized Glipr1l1 role. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG CONTEXT OR TISSUE MISMATCH ROLE CONFLATION Sources checked: MGI:MGI:1916536 · mouse Glipr1l1 SUPPORTS SOURCE BUT NOT TARGET Mouse Glipr1l1 participates in an IZUMO1-containing sperm complex, but that paralog-specific mechanism has not been demonstrated for GLIPR1L2. PANTHER:PTN000036124 · broad PTHR10334 ancestral node UNRESOLVED This node spans functionally divergent CAP-family proteins and is too broad for transfer of the Glipr1l1-specific adaptor role. Supporting Evidence: PMID:31672133 At least two of these complexes contain IZUMO1 in partnership with GLI pathogenesis-related 1 like 1 (GLIPR1L1). file:human/GLIPR1L2/GLIPR1L2-notes.md The only PAINT experimental seed is mouse Glipr1l1, whose adaptor-like activity is tied to an IZUMO1-containing sperm complex. file:human/GLIPR1L2/GLIPR1L2-deep-research-manual.md Shared CAP architecture therefore does not justify transferring the specialized sperm molecular-adaptor role to GLIPR1L2. |
| GO:0016020 membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping calls GLIPR1L2 a single-pass membrane protein, consistent with the predicted hydrophobic helix at residues 254–274. Reason: A clear transmembrane segment supports generic membrane association even though the exact organelle, topology, and isoform-specific localization have not been established. The broad GO:0016020 term does not overstate those details. Supporting Evidence: file:human/GLIPR1L2/GLIPR1L2-uniprot.txt FT TRANSMEM 254..274 |
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Download this section (compressed HTML)Q: Which GLIPR1L2 isoforms are translated in human germ cells and somatic tissues, and which are stable membrane proteins?
Q: Is the CAP domain extracellular, organelle-luminal, or cytosolic in each major isoform, and does any isoform undergo secretion or proteolytic release?
Q: Does GLIPR1L2 form a reproducible endogenous complex with PECAM1, UBE2K, VIM, or reproductive proteins, and what activity follows from that complex?
Experiment: Use long-read RNA sequencing and targeted proteomics to identify translated isoforms, then create isoform-specific endogenous tags. Combine surface biotinylation, selective permeabilization, protease protection, glycosidase sensitivity, and knockout-controlled microscopy to resolve compartment and topology.
Hypothesis: Major GLIPR1L2 splice isoforms occupy different membranes or topologies.
Type: Isoform-resolved expression and membrane-topology mapping
Experiment: Endogenously tag GLIPR1L2 in a validated human testis/germ-cell model and a GLIPR1L2-positive somatic model, perform affinity purification-mass spectrometry and proximity labeling, and validate candidates reciprocally. Compare all major isoforms and explicitly test PECAM1, UBE2K, VIM, and IZUMO-family proteins.
Hypothesis: GLIPR1L2 participates in a specific native complex that is not captured by the paralog-derived molecular-adaptor annotation.
Type: Endogenous interactome mapping and orthogonal validation
Experiment: Generate GLIPR1L2-null human germ-cell differentiation models with isoform-specific rescue and quantify differentiation, acrosomal markers, membrane remodeling, cell viability, and interaction phenotypes. In mouse, compare a Glipr1l2-only knockout with the published cluster deletion under sensitized reproductive assays.
Hypothesis: GLIPR1L2 has a subtle or redundant germ-cell function not detected by the mouse three-gene cluster fertility screen.
Type: Gene-specific loss-of-function, rescue, and sensitized phenotyping
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: GLIPR1L2's direct molecular activity, native interaction complex, and physiological biological process are unknown.
OPEN BIOLOGYCURATION WHOLLY_DARK
What is known: Sequence architecture, p53-responsive transcription, tissue expression, and several high-throughput interactions are known, but none defines what endogenous GLIPR1L2 does.
Significance: Resolving this gap is necessary to determine whether GLIPR1L2 is a receptor, ligand, organizer, or another kind of CAP-family membrane protein and to replace the unsupported adaptor transfer with a specific activity if one exists.
What would resolve it: Endogenous interaction mapping, loss-of-function/rescue phenotyping, and biochemical reconstitution in a verified GLIPR1L2-expressing human cell context.
Provenance (the field's own admissions):
Gap: The membrane topology, compartment, and isoform-specific localization of GLIPR1L2 have not been established experimentally.
OPEN BIOLOGYCURATION CC_DARK
What is known: A transmembrane helix is predicted for the canonical protein, but the extracellular IBA, N-terminal CAP-domain orientation, and localization of the six splice forms remain unverified.
Significance: Topology determines whether the CAP domain could act extracellularly or in an organelle lumen and is required to adjudicate the extracellular-region IBA.
What would resolve it: Perform isoform-resolved protease-protection, surface-labeling, glycosylation, and microscopy experiments using endogenous tags and knockout controls.
Provenance (the field's own admissions):
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