NAALADL2 (inactive N-acetylated-alpha-linked acidic dipeptidase-like protein 2) is a predicted single-pass type II membrane glycoprotein of the M28 metallopeptidase family (M28B subfamily, related to glutamate carboxypeptidase II / NAALADase / PSMA and, more distantly, the transferrin receptors). Unlike active family members, NAALADL2 lacks the conserved zinc-binding and active-site residues and is predicted to be catalytically inactive (no peptidase/hydrolase activity). Its molecular function is not established. The gene spans a very large (1.37 Mb), structurally variable, extensively alternatively spliced locus at 3q26.3 that is severed by a Cornelia de Lange-associated translocation breakpoint (though no CdLS point mutations were found), and it has been linked through genetic association to several traits and cancers. Expression is strongest in kidney and placenta, with embryonic expression in duodenal and stomach endoderm, mesonephros, metanephros and pancreas, but a defined biochemical or cellular role for the protein remains unknown.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016020 membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Membrane localization (IEA); UniProt predicts a single-pass type II membrane protein. The falcon deep research likewise infers a likely membrane-associated/extracellularly-exposed localization by family analogy (it provides no direct experimental localization for NAALADL2). Reason: Consistent with predicted topology; core localization. Family analogy (M28B/PSMA) supports a membrane-associated rather than soluble cytosolic localization, though direct experimental evidence for NAALADL2 is lacking. Supporting Evidence: file:human/NAALADL2/NAALADL2-uniprot.txt Single-pass type II file:human/NAALADL2/NAALADL2-deep-research-falcon.md support a likely **membrane-associated and/or extracellularly exposed** localization rather than a soluble cytosolic enzyme |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Generic 'protein binding' from a large-scale binary interactome screen (Rolland et al. 2014). The five IntAct-curated partners behind the five GOA rows - GPR25 (O00155), GRM2 (Q14416), LAPTM4B (Q86VI4), SLC30A3 (Q99726) and ITM2B (Q9Y287) - are all integral membrane proteins detected by yeast two-hybrid, a system with well-known limitations for transmembrane baits, and none has any established functional connection to NAALADL2. Reason: High-throughput Y2H evidence, uninformative 'protein binding' term, and partners (all polytopic/single-pass membrane proteins with no shared pathway) that suggest sticky-bait artifact rather than a defined molecular function; over-annotation per project guidance discouraging bare protein binding. Supporting Evidence: file:human/NAALADL2/NAALADL2-uniprot.txt Q58DX5; O00155: GPR25; NbExp=3; IntAct=EBI-10178964, EBI-10178951; |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | MARK AS OVER ANNOTATED | Summary: Nucleoplasm (IDA from immunofluorescence/HPA). This conflicts with the UniProt prediction of a single-pass type II membrane protein; the antibody-based localization is not obviously reconcilable with the predicted topology. Reason: HPA antibody-based nuclear signal directly conflicts with the predicted single-pass type II membrane topology; antibody-based nuclear staining of predicted membrane proteins is a known artifact source. Treat as over-annotation pending orthogonal confirmation. Supporting Evidence: file:human/NAALADL2/NAALADL2-uniprot.txt Single-pass type II |
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Download this section (compressed HTML)Q: Does NAALADL2 retain any residual substrate binding (without catalysis), and what is its true subcellular localization given the conflict between predicted membrane topology and the reported nucleoplasm staining?
Experiment: Determine NAALADL2 topology and localization with tagged constructs and confirm absence of NAALADase activity in a peptidase assay; pull down interactors to probe for a scaffolding function.
Hypothesis: NAALADL2 is a catalytically dead membrane protein with a non-enzymatic (e.g. adhesion/scaffold) role.
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