VMA22 encodes a dedicated endoplasmic-reticulum-associated assembly factor for the vacuolar proton-translocating V-type ATPase. Vma22 is not a mature V-ATPase subunit. Instead, it associates with Vma12 in a stable ER membrane assembly complex that transiently contacts the newly synthesized Vph1/V0 sector subunit, stabilizing V0 assembly intermediates before export to the vacuole. Loss of VMA22 blocks V-ATPase assembly and activity and causes vacuolar acidification defects.
Definition: Binding to and stabilizing V-type ATPase V0-sector assembly intermediates during biogenesis of the vacuolar proton-transporting V-type ATPase complex.
Justification: Vma22 has a clear molecular role as part of the ER-localized Vma12-Vma22 assembly complex that transiently binds Vph1/V0-sector intermediates, but current GO terms capture only the biological process or the Vma12-Vma22 complex. Generic protein folding chaperone terms would overstate Vma22 as a general foldase rather than a V-ATPase assembly factor.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0051082 unfolded protein binding | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: The PANTHER/IBA unfolded protein binding annotation reflects transfer from assembly-factor biology but overstates Vma22 as a general unfolded-protein binding chaperone. Reason: Vma22 acts in a dedicated Vma12-Vma22 ER assembly complex for the V-ATPase V0 sector, and the authors explicitly distinguish these assembly factors from general molecular chaperones. Their proposed model places a fully translocated and folded Vph1 client at the interaction step, while the experiments establish stabilization and assembly rather than client folding. GO:0051082 is obsolete. GO:0044183 protein folding chaperone is not proposed because no assistance of protein folding was demonstrated. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN001592797 · PANTHER:PTN001592797 SOURCE STALE OR MISSING The exact PTN is present in the pinned GOA WITH/FROM, but it is absent from the current local PAINT snapshot, so its ancestral assertion cannot be recovered for direct inspection. SGD:S000001102 · VMA22 SOURCE WEAK OR INFERRED VMA22 is a legitimate target-descendant source rather than a circular donor, but its experimental assembly phenotypes support only a dedicated stabilization/assembly role and are over-scoped when used to seed unfolded-protein binding. Supporting Evidence: PMID:9660861 Unlike general molecular chaperones such as Kar2p/BiP (Gething and Sambrook, 1992), Vma12p, Vma21p, and Vma22p represent a class of ER resident proteins dedicated to the assembly of a specific enzyme complex, the V-ATPase. PMID:9660861 The first step in the assembly pathway would involve the association of the fully translocated and folded Vph1p with the Vma12p/Vma22p assembly complex in the ER membrane. PMID:9660861 We conclude that the interaction of Vph1p with the assembly complex stabilizes this Vo subunit in the ER allowing it to assemble into the Vo subcomplex. file:yeast/VMA22/VMA22-deep-research-falcon.md **VMA22 (P38784/YHR060W)** encodes **Vma22p**, an **ER-associated peripheral assembly factor** required for **V-ATPase V0-region biogenesis**. |
| GO:1990871 Vma12-Vma22 assembly complex | IBA GO_REF:0000033 | ACCEPT | Summary: The IBA annotation to the Vma12-Vma22 assembly complex is consistent with direct biochemical evidence that Vma12 and Vma22 form a stable ER-localized assembly complex. Reason: Vma12-Vma22 complex membership is a core feature of Vma22 function and is supported by both family-transfer and direct experimental evidence. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001278552 · PANTHER:PTN001278552 SOURCE STALE OR MISSING The exact PTN is recorded in the pinned GOA WITH/FROM but is absent from the current local PAINT snapshot; independent Vma22-specific biochemical evidence nevertheless establishes the complex membership. SGD:S000001102 · VMA22 SUPPORTS TRANSFER The target's own direct evidence validly grounds the ancestral inference: Vma12 and Vma22 interact and form the named stable complex. Supporting Evidence: PMID:9660861 Vma12p and Vma22p form a stable membrane associated complex. |
| GO:0070072 vacuolar proton-transporting V-type ATPase complex assembly | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro transfer to V-ATPase complex assembly is consistent with direct yeast genetic and biochemical evidence for Vma22. Reason: Although this particular annotation is electronic, it matches the experimentally demonstrated core role of Vma22 in V-ATPase assembly. Supporting Evidence: PMID:7673216 vma22 delta cells contain no V-ATPase activity due to a failure to assemble the enzyme complex. |
| GO:0005634 nucleus | HDA PMID:26928762 One library to make them all: streamlining the creation of y... | UNDECIDED | Summary: The nucleus annotation comes from a high-throughput tagged-protein library, whereas focused biochemical studies establish ER membrane association. The cached article lacks the VMA22-specific supplementary localization record, so the experimental HDA call cannot be adjudicated directly. Reason: ER localization is strongly supported and is the known site of function, but it does not logically exclude a minor or tag-dependent nuclear signal. The study used amino-terminal GFP tagging and manual localization without co-localization markers; an amino-terminal fusion is a concrete caveat for VMA22 because UniProt records alternative initiation products. The cached main text does not expose the VMA22-specific observation, so this experimental row is retained as UNDECIDED rather than removed. Supporting Evidence: PMID:26928762 To establish this strategy we constructed a library containing ~1,800 strains where all proteins with known or predicted localization to the yeast endomembrane system are tagged with an amino terminal (N′) SWAT acceptor module. The used module also contains a constitutive promoter and a GFP tag. PMID:26928762 Since no co-localization markers were used we only assigned localizations that could be easily discriminated by eye: ER, nuclear periphery, cytosol, cell periphery, vacuole lumen, vacuole membrane, mitochondria, nucleus, bud/bud neck and punctate PMID:7673216 Vma22p is a 21-kDa hydrophilic protein that is not a subunit of the V-ATPase but rather is associated with ER membranes. |
| GO:1990871 Vma12-Vma22 assembly complex | IPI PMID:9660861 Assembly of the yeast vacuolar H+-ATPase occurs in the endop... | ACCEPT | Summary: Direct interaction and cofractionation evidence supports Vma22 as part of the Vma12-Vma22 assembly complex. Reason: This is a precise cellular-component/complex annotation for Vma22's core assembly-factor role. Supporting Evidence: PMID:9660861 Vma12p and Vma22p were found to interact directly as determined by chemical cross-linking analysis and cofractionation under conditions of gentle detergent solubilization. |
| GO:0007035 vacuolar acidification | IMP PMID:1628805 Genes required for vacuolar acidity in Saccharomyces cerevis... | KEEP AS NON CORE | Summary: VMA22 was identified among VPH/VMA genes required for vacuolar acidity. The phenotype is a downstream consequence of failed V-ATPase assembly. Reason: Vacuolar acidification is a valid biological-process outcome of Vma22 function, but the mechanistic core should be understood as V-ATPase assembly rather than proton transport by Vma22 itself. Supporting Evidence: PMID:1628805 Thirty nine vacuolar pH (Vph-) mutants were identified. |
| GO:0051082 unfolded protein binding | IMP PMID:7673216 Vma22p is a novel endoplasmic reticulum-associated protein r... | MARK AS OVER ANNOTATED | Summary: The 1995 Vma22 paper supports a V-ATPase assembly factor role, not generic unfolded protein binding. Reason: GO:0051082 is obsolete. Vma22 is ER-associated and required for V-ATPase assembly, but the evidence does not show broad binding to unfolded proteins. Later full-text work distinguishes Vma22 from general chaperones and proposes that its Vph1 client is folded at association. Although the complex stabilizes Vph1, GO:0044183 protein folding chaperone is not proposed because the experiments establish assembly and stability rather than client folding. Supporting Evidence: PMID:7673216 Vma22p is a 21-kDa hydrophilic protein that is not a subunit of the V-ATPase but rather is associated with ER membranes. PMID:9660861 The first step in the assembly pathway would involve the association of the fully translocated and folded Vph1p with the Vma12p/Vma22p assembly complex in the ER membrane. |
| GO:0051082 unfolded protein binding | IMP PMID:8582630 vph6 mutants of Saccharomyces cerevisiae require calcineurin... | MARK AS OVER ANNOTATED | Summary: VPH6/VMA22 mutant phenotypes support defective V-ATPase assembly rather than a standalone unfolded-protein binding activity. Reason: GO:0051082 is obsolete, and this annotation generalizes a specific assembly-factor defect into a broad chaperone-like molecular function. GO:0044183 protein folding chaperone is not proposed because this mutant study establishes failed V-ATPase assembly, not assistance of client protein folding. Supporting Evidence: PMID:8582630 vph6 mutant strains fail to assemble the vacuolar H(+)-ATPase (V-ATPase). |
| GO:0070072 vacuolar proton-transporting V-type ATPase complex assembly | IMP PMID:7673216 Vma22p is a novel endoplasmic reticulum-associated protein r... | ACCEPT | Summary: Vma22 is required for V-ATPase complex assembly; vma22 deletion eliminates V-ATPase activity because the enzyme complex fails to assemble. Reason: This is the central experimentally supported biological process for Vma22. Supporting Evidence: PMID:7673216 vma22 delta cells contain no V-ATPase activity due to a failure to assemble the enzyme complex. |
| GO:0005789 endoplasmic reticulum membrane | IDA | NEW | Summary: A new ER membrane annotation is warranted because focused biochemical work shows Vma22 is associated with ER membranes through Vma12-dependent assembly complex formation. Reason: Existing GOA contains an unresolved high-throughput nucleus annotation but lacks the experimentally supported ER membrane localization. Vma22 is hydrophilic but membrane-associated in the ER via the Vma12-Vma22 assembly complex. Supporting Evidence: PMID:7673216 Vma22p is a 21-kDa hydrophilic protein that is not a subunit of the V-ATPase but rather is associated with ER membranes. PMID:9660861 Vma12p together with Vma22p forms an assembly complex that interacts with Vo subunits in the ER as they are being assembled before transport of the V-ATPase complex to the vacuole. |
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Download this section (compressed HTML)Q: What is the precise structural interface by which the Vma12-Vma22 complex contacts Vph1 or other V0-sector assembly intermediates?
Q: Does Vma22 have any separable function outside the Vma12-Vma22 assembly complex, or is all detectable Vma22 activity complex-dependent?
Q: Which VMA22 isoform(s), if any, are functional in V-ATPase assembly, and do the alternative initiation products differ in stability or assembly-complex incorporation?
Q: Does amino-terminal tagging alter Vma22 isoform usage, ER association, or localization and account for the high-throughput nuclear signal?
Experiment: Use structure-guided Vma22 mutants to disrupt Vma12 binding or Vph1 interaction separately, then measure V0 assembly, Vph1 stability, and vacuolar acidification.
Type: genetics
Experiment: Reconstitute the Vma12-Vma22 complex with Vph1/V0 assembly intermediates and map transient contacts by crosslinking mass spectrometry or cryo-EM.
Type: biochemistry
Experiment: Test the UniProt alternative initiation isoforms for expression, ER membrane association, Vma12 binding, and complementation of vma22 deletion phenotypes.
Type: cell biology
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