LY6/PLAUR domain-containing protein 2, member of the Ly6/uPAR superfamily characterized by a three-finger LU domain (snake toxin-like fold) stabilized by disulfide bonds. Encoded in the chromosome 8q24.3 LY6 cluster (with PSCA, LY6K, SLURP1, LYNX1, LY6D, LY6E, LY6H, GPIHBP1). Predicted GPI-anchored cell-surface protein based on family architecture; direct biochemical confirmation of the GPI anchor for human LYPD2 is lacking. RNA is most highly expressed in esophagus (greater than 250 TPM in GTEx), with lower expression in skin and vagina. Curated LY6-family summaries note "no known or proposed function" for human LYPD2; the most concrete functional hypothesis comes from a mouse Ly6/uPAR review listing alpha4-beta2 nicotinic acetylcholine receptors (nAChRs) as the interacting factor and "nAChR Modulator" as the cellular function (Loughner 2016, Table 3). A 2022 mouse co-IP study (Lauriello et al.) reported no interaction between lypd2 and homomeric GluR2Q/GluR2R AMPA receptors, narrowing but not refuting the receptor-modulator hypothesis. LYPD2 was also identified in all four focused CRISPR screens of GPI-anchored proteins as a top-10 enriched host factor in coronavirus infection (Ma et al. 2025), and is used as a marker gene for a non-classical monocyte subset in integrated autoimmune-disease scRNA-seq. Mechanistic function (binding partners, pathway role) remains a high-priority experimental gap.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane - GPI-anchored to membrane. Consistent with Ly6/uPAR family architecture; curated human LY6 family tables explicitly annotate LYPD2 as cell surface. Reason: Core localization supported by family-level architecture and curated LY6 family summaries. Supporting Evidence: file:human/LYPD2/LYPD2-deep-research-openai.md See deep research file for comprehensive analysis PMID:27098205 LYPD2YesUnknownฮฑ4ฮฒ2 nAChRsnAChR ModulatorNoYes |
| GO:0098552 side of membrane | IEA GO_REF:0000043 | ACCEPT | Summary: Side of membrane - GPI-anchored to the extracellular (outer) leaflet of the plasma membrane by family analogy with other Ly6/uPAR proteins. Reason: Core localization. Family-level evidence supports outer-leaflet tethering via a C-terminal GPI anchor. Supporting Evidence: PMID:36441793 Ly6 proteins are generally found within the extracellular space, either as a secreted protein or (in the majority of cases) by being physically tethered to the outer leaflet of the plasma membrane by a post-translational C-terminal GPI anchor modification |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Protein binding - interacts with receptors or partners. The most concrete (mouse) functional hypothesis is that LYPD2 modulates ฮฑ4ฮฒ2 nAChRs; however, a 2022 study found no interaction with GluR2Q/GluR2R AMPA receptor homomers, so direct human binding partners remain to be defined. Reason: Per CLAUDE.md, the generic GO:0005515 (protein binding) term should be avoided. The IPI evidence is from a high-throughput binary interactome screen (HuRI) without a specifically validated LYPD2 interaction partner and without functional context. The nAChR-modulator hypothesis is mouse-only and speculative for human LYPD2; the negative AMPA result narrows but does not establish a specific partner (PR #771 review feedback). Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8940388 | ACCEPT | Summary: Extracellular region - GPI-anchored extracellular protein, consistent with Ly6/uPAR family localization. Reason: Core localization. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8940388 | ACCEPT | Summary: Plasma membrane - GPI-anchored to membrane. Reason: Core localization. |
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Download this section (compressed HTML)Q: What is the molecular function of LYPD2 and which receptors or ligands does it interact with?
Suggested experts: Cell signaling researchers, Immunologists
Q: Does human LYPD2 modulate ฮฑ4ฮฒ2 (or other) nicotinic acetylcholine receptors, as suggested by the mouse Ly6/uPAR family table?
Suggested experts: Neuroscience / nAChR specialists
Q: Does LYPD2 act as a coronavirus host restriction or entry factor in esophageal epithelium, consistent with its enrichment in focused GPI-anchored-protein CRISPR screens?
Suggested experts: Virologists / host-pathogen genomics
Experiment: Co-immunoprecipitation and electrophysiology in heterologous cells to test whether human LYPD2 modulates ฮฑ4ฮฒ2 (and other) nAChRs.
Hypothesis: LYPD2 modulates ฮฑ4ฮฒ2 nAChR function analogously to mouse Lypd2.
Type: biochemistry / electrophysiology
Experiment: PI-PLC sensitivity assay and surface labeling in esophageal epithelial cells (and non-classical monocytes) to biochemically confirm GPI anchoring and outer-leaflet localization of human LYPD2.
Hypothesis: Human LYPD2 is GPI-anchored to the outer leaflet of the plasma membrane.
Type: cell biology / biochemistry
Experiment: CRISPR knockout / rescue of LYPD2 in coronavirus infection models to test whether the screen-hit phenotype reflects a direct antiviral or pro-viral role.
Hypothesis: LYPD2 contributes to coronavirus infection susceptibility or restriction in human cells.
Type: functional genomics / virology
Experiment: AP-MS or proximity labeling (e.g. BioID) in esophageal epithelial cells to identify LYPD2 binding partners.
Hypothesis: LYPD2 interacts with cell surface receptors or ligands.
Type: proteomics
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