VPS-15 (ZK930.1) is the C. elegans ortholog of yeast Vps15 and human PIK3R4/p150, a 1354-residue regulatory subunit of the class III phosphatidylinositol 3-kinase. It has an N-terminal pseudokinase domain, a central HEAT-repeat region and a C-terminal WD40 domain. With the lipid kinase VPS-34 and BEC-1/Beclin it forms the core of two complexes. Complex I (with EPG-8/ATG14) makes phosphatidylinositol 3-phosphate (PI3P) to nucleate autophagosomes. Complex II (with UVRAG) acts in endosome maturation and endosome-to-lysosome traffic. By analogy with human VPS15, the pseudokinase domain probably binds GTP and controls VPS-34 activity allosterically, rather than phosphorylating protein substrates. Experimental data on the worm protein itself are sparse.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000425 pexophagy | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Pexophagy, seeded by yeast/fungal Vps15 data. Reason: As a subunit of PI3KC3-C1, VPS-15 is plausibly required for all forms of macroautophagy, including selective forms; no worm-specific data. Supporting Evidence: PMID:39913640 The class III phosphatidylinositol-3 kinase complexes I and II (PI3KC3-C1 and PI3KC3-C2) have vital roles in macroautophagy and endosomal maturation, respectively |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | REMOVE | Summary: InterPro protein kinase domain mapping. Reason: The VPS15 N-terminal domain is a pseudokinase. In human PI3KC3-C1 it binds GTP, not ATP, and acts as an allosteric regulator of VPS34 rather than a protein kinase (PMID:39913640). Worm VPS-15 keeps the arginine gatekeeper that sets GTP specificity and is well conserved in this region (file:worm/vps-15/vps-15-bioinformatics/RESULTS.md). There is no worm biochemical evidence of protein kinase activity. Domain-signature and phylogenetic transfer of catalytic kinase activity is therefore removed, consistent with the human PIK3R4 review. Supporting Evidence: PMID:39913640 Finally, we found that VPS15PKD is an unusual pseudokinase that binds GTP instead of ATP file:worm/vps-15/vps-15-bioinformatics/RESULTS.md C. elegans VPS-15 keeps an arginine at the equivalent position (R101) |
| GO:0004674 protein serine/threonine kinase activity | IBA GO_REF:0000033 | REMOVE | Summary: Ser/Thr kinase activity inferred for the VPS15 family. Reason: The VPS15 N-terminal domain is a pseudokinase. In human PI3KC3-C1 it binds GTP, not ATP, and acts as an allosteric regulator of VPS34 rather than a protein kinase (PMID:39913640). Worm VPS-15 keeps the arginine gatekeeper that sets GTP specificity and is well conserved in this region (file:worm/vps-15/vps-15-bioinformatics/RESULTS.md). There is no worm biochemical evidence of protein kinase activity. Domain-signature and phylogenetic transfer of catalytic kinase activity is therefore removed, consistent with the human PIK3R4 review. Propagation Review Root cause: PROPAGATION BAD Failure modes: PSEUDO OR SUBACTIVITY LOSS Sources checked: PANTHER:PTN000426471 · PTN000426471 SUPPORTS SOURCE BUT NOT TARGET VPS15 family node; protein kinase activity rests on early yeast Vps15 data, whereas structural work shows the conserved domain is a GTP-binding pseudokinase. Supporting Evidence: PMID:39913640 Finally, we found that VPS15PKD is an unusual pseudokinase that binds GTP instead of ATP PMID:39913640 This directly confirmed that the dominant nucleotide present was GTP, with no detectable ATP or ADP file:worm/vps-15/vps-15-bioinformatics/RESULTS.md C. elegans VPS-15 keeps an arginine at the equivalent position (R101) |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | REMOVE | Summary: Automated Ser/Thr kinase activity (EC 2.7.11.1 from PROSITE rule). Reason: The VPS15 N-terminal domain is a pseudokinase. In human PI3KC3-C1 it binds GTP, not ATP, and acts as an allosteric regulator of VPS34 rather than a protein kinase (PMID:39913640). Worm VPS-15 keeps the arginine gatekeeper that sets GTP specificity and is well conserved in this region (file:worm/vps-15/vps-15-bioinformatics/RESULTS.md). There is no worm biochemical evidence of protein kinase activity. Domain-signature and phylogenetic transfer of catalytic kinase activity is therefore removed, consistent with the human PIK3R4 review. Supporting Evidence: PMID:39913640 Finally, we found that VPS15PKD is an unusual pseudokinase that binds GTP instead of ATP file:worm/vps-15/vps-15-bioinformatics/RESULTS.md C. elegans VPS-15 keeps an arginine at the equivalent position (R101) |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: ATP binding inferred from the kinase-domain signature. Reason: The human VPS15 pseudokinase domain binds GTP with no detectable ATP; the worm gatekeeper arginine is conserved. Nucleotide binding is likely, but ATP is probably the wrong nucleotide; no worm data. Supporting Evidence: PMID:39913640 This directly confirmed that the dominant nucleotide present was GTP, with no detectable ATP or ADP file:worm/vps-15/vps-15-bioinformatics/RESULTS.md C. elegans VPS-15 keeps an arginine at the equivalent position (R101) |
| GO:0005770 late endosome | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Late endosome localization of the VPS15/PI3KC3-C2 complex. Reason: PI3KC3-C2 acts in endosome maturation; in worms BEC-1 and VPS-34 regulate endosomal PI3P. Non-core relative to autophagy. Supporting Evidence: PMID:39913640 The class III phosphatidylinositol-3 kinase complexes I and II (PI3KC3-C1 and PI3KC3-C2) have vital roles in macroautophagy and endosomal maturation, respectively PMID:26783301 the class III PI3K complex, which is composed of VPS-34, BEC-1, and VPS-15/p150 |
| GO:0005776 autophagosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt ARBA location: autophagosome. Reason: The complex acts on omegasome/phagophore membranes during nucleation; autophagosome association is non-core. Supporting Evidence: file:worm/vps-15/vps-15-uniprot.txt Cytoplasmic vesicle, autophagosome |
| GO:0006623 protein targeting to vacuole | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Protein targeting to vacuole (yeast CPY sorting by Vps15/Vps34). Reason: Endosomal sorting role of PI3KC3-C2 is conserved; the yeast-centric vacuole term is acceptable for lysosomal targeting but non-core. Supporting Evidence: PMID:39913640 The class III phosphatidylinositol-3 kinase complexes I and II (PI3KC3-C1 and PI3KC3-C2) have vital roles in macroautophagy and endosomal maturation, respectively |
| GO:0016236 macroautophagy | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based macroautophagy. Reason: VPS-15 is the regulatory/scaffold subunit of the autophagy PI3K complex. Supporting Evidence: PMID:26783301 the class III PI3K complex, which is composed of VPS-34, BEC-1, and VPS-15/p150 PMID:39913640 The class III phosphatidylinositol-3 kinase complexes I and II (PI3KC3-C1 and PI3KC3-C2) have vital roles in macroautophagy and endosomal maturation, respectively |
| GO:0016301 kinase activity | IEA GO_REF:0000104 | REMOVE | Summary: Generic kinase activity from UniRule/keyword mapping. Reason: The VPS15 N-terminal domain is a pseudokinase. In human PI3KC3-C1 it binds GTP, not ATP, and acts as an allosteric regulator of VPS34 rather than a protein kinase (PMID:39913640). Worm VPS-15 keeps the arginine gatekeeper that sets GTP specificity and is well conserved in this region (file:worm/vps-15/vps-15-bioinformatics/RESULTS.md). There is no worm biochemical evidence of protein kinase activity. Domain-signature and phylogenetic transfer of catalytic kinase activity is therefore removed, consistent with the human PIK3R4 review. Supporting Evidence: PMID:39913640 Finally, we found that VPS15PKD is an unusual pseudokinase that binds GTP instead of ATP file:worm/vps-15/vps-15-bioinformatics/RESULTS.md C. elegans VPS-15 keeps an arginine at the equivalent position (R101) |
| GO:0016740 transferase activity | IEA GO_REF:0000104 | REMOVE | Summary: Transferase activity from keyword mapping. Reason: Derived from the kinase keyword; the domain is a pseudokinase with no demonstrated transferase activity. The VPS15 N-terminal domain is a pseudokinase. In human PI3KC3-C1 it binds GTP, not ATP, and acts as an allosteric regulator of VPS34 rather than a protein kinase (PMID:39913640). Worm VPS-15 keeps the arginine gatekeeper that sets GTP specificity and is well conserved in this region (file:worm/vps-15/vps-15-bioinformatics/RESULTS.md). There is no worm biochemical evidence of protein kinase activity. Domain-signature and phylogenetic transfer of catalytic kinase activity is therefore removed, consistent with the human PIK3R4 review. Supporting Evidence: PMID:39913640 Finally, we found that VPS15PKD is an unusual pseudokinase that binds GTP instead of ATP |
| GO:0034271 phosphatidylinositol 3-kinase complex, class III, type I | IBA GO_REF:0000033 | ACCEPT | Summary: VPS15 is a core subunit of PI3KC3-C1 (with VPS34, Beclin/BEC-1 and ATG14/EPG-8). Reason: Core complex for autophagosome nucleation; worm literature describes the complex as VPS-34, BEC-1 and VPS-15. Supporting Evidence: PMID:26783301 the class III PI3K complex, which is composed of VPS-34, BEC-1, and VPS-15/p150 PMID:39913640 The VPS15 pseudokinase domain binds tightly to guanosine triphosphate and stabilizes a web of interactions to autoinhibit the cytosolic complex and promote activation upon membrane binding |
| GO:0034272 phosphatidylinositol 3-kinase complex, class III, type II | IBA GO_REF:0000033 | ACCEPT | Summary: VPS15 is a core subunit of PI3KC3-C2 (with UVRAG). Reason: Conserved endosomal complex. Supporting Evidence: PMID:39913640 The class III phosphatidylinositol-3 kinase complexes I and II (PI3KC3-C1 and PI3KC3-C2) have vital roles in macroautophagy and endosomal maturation, respectively PMID:26783301 the class III PI3K complex, which is composed of VPS-34, BEC-1, and VPS-15/p150 |
| GO:0045324 late endosome to vacuole transport | IBA GO_REF:0000033 | ACCEPT | Summary: VPS15 family role in late endosome to vacuole transport. Reason: As above; conserved PI3KC3-C2 function. Supporting Evidence: PMID:39913640 The class III phosphatidylinositol-3 kinase complexes I and II (PI3KC3-C1 and PI3KC3-C2) have vital roles in macroautophagy and endosomal maturation, respectively |
| GO:0045324 late endosome to vacuole transport | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based late endosome to vacuole transport. Reason: Endosomal role of PI3KC3-C2, the second core function of VPS15 complexes; in animals the vacuole term covers transport to the lysosome. Supporting Evidence: PMID:39913640 The class III phosphatidylinositol-3 kinase complexes I and II (PI3KC3-C1 and PI3KC3-C2) have vital roles in macroautophagy and endosomal maturation, respectively |
| GO:0071561 nucleus-vacuole junction | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Nucleus-vacuole junction, seeded by yeast Vps15. Reason: The nucleus-vacuole junction is a fungal membrane contact site formed by Vac8 and Nvj1; there is no evidence for it in C. elegans. Propagation Review Root cause: PROPAGATION BAD Failure modes: LINEAGE OR TAXON MISMATCH Sources checked: PANTHER:PTN000426471 · PTN000426471 SUPPORTS SOURCE BUT NOT TARGET VPS15 node; the nucleus-vacuole junction is a fungal-specific contact site. Supporting Evidence: PMID:39913640 The class III phosphatidylinositol-3 kinase complexes I and II (PI3KC3-C1 and PI3KC3-C2) have vital roles in macroautophagy and endosomal maturation, respectively |
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Download this section (compressed HTML)Q: Does C. elegans VPS-15 bind GTP rather than ATP, as human VPS15 does, and is it N-myristoylated like the human protein?
Q: Which vps-15 phenotypes (autophagy, endosome maturation, cell corpse clearance) does a vps-15 null show, compared with bec-1 and vps-34 nulls?
Experiment: Nucleotide-release HPLC/MS on purified worm VPS-34/VPS-15/BEC-1 complex, and an R101 gatekeeper mutant tested for rescue of vps-15 mutant autophagy and endosome phenotypes.
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