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. The evidence supports specific assembly-intermediate binding, not broad 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. 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. 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...	REMOVE	Summary: The nucleus annotation is from a high-throughput localization resource and conflicts with focused biochemical evidence that Vma22 is ER-associated. Reason: Vma22's established function is in the ER-localized Vma12-Vma22 assembly complex. No gene-specific evidence supports nuclear localization as a site of Vma22 function. 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.
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...	ACCEPT	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: Vma22 is ER-associated and required for V-ATPase assembly, but the evidence does not show broad binding to unfolded proteins. The assembly process and Vma12-Vma22 complex annotations capture the biology more accurately. 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.
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: This annotation generalizes a specific assembly-factor defect into a broad chaperone-like molecular function. V-ATPase complex assembly is the defensible process annotation. 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 a misleading 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.

📚 Additional Documentation

Deep Research Falcon

(VMA22-deep-research-falcon.md)

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organism_full: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P38784
Protein Description: RecName: Full=Vacuolar ATPase assembly protein VMA22;
Gene Information: Name=VMA22; OrderedLocusNames=YHR060W;
Organism (full): Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
Protein Family: Not specified in UniProt
Key Domains: Vma22/CCDC115. (IPR040357); Vma22_CCDC115 (PF21730)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "VMA22" matches the protein description above
Verify the organism is correct: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'VMA22' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene VMA22 (gene ID: VMA22, UniProt: P38784) in yeast.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P38784
Protein Description: RecName: Full=Vacuolar ATPase assembly protein VMA22;
Gene Information: Name=VMA22; OrderedLocusNames=YHR060W;
Organism (full): Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
Protein Family: Not specified in UniProt
Key Domains: Vma22/CCDC115. (IPR040357); Vma22_CCDC115 (PF21730)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "VMA22" matches the protein description above
Verify the organism is correct: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene VMA22 (gene ID: VMA22, UniProt: P38784) in yeast.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Research report: Saccharomyces cerevisiae VMA22 (UniProt P38784; ORF YHR060W) — functional annotation

0) Target verification (critical disambiguation)

The literature reviewed here matches the UniProt target identity: VMA22 = YHR060W encoding Vacuolar ATPase assembly protein Vma22p in Saccharomyces cerevisiae (S288c). Hill & Stevens explicitly state that VMA22 is identical to YHR060W and characterize the encoded protein as an ER-associated V-ATPase assembly factor (~21 kDa) rather than a V-ATPase subunit (published 1995-09, J Biol Chem, https://doi.org/10.1074/jbc.270.38.22329) (hill1995vma22pisa pages 1-1). Subsequent mechanistic work on Vma12p/Vma22p and recent cryo-EM structures examine the same yeast proteins and assembly pathway (published 1998-07, J Cell Biol, https://doi.org/10.1083/jcb.142.1.39; published 2023-02, PNAS, https://doi.org/10.1073/pnas.2217181120) (graham1998assemblyofthe pages 1-2, wang2023structuralbasisof pages 1-2).

1) Key concepts and definitions (current understanding)

1.1 V-ATPase architecture and why assembly factors matter

The vacuolar H+-ATPase (V-ATPase) is a rotary proton pump composed of a soluble catalytic V1 sector and a membrane-embedded V0 sector. A central cell-biological constraint is that V0 is assembled in the ER membrane, while the complete proton pump must be prevented from acidifying the ER; thus, eukaryotes use dedicated assembly factors that are not part of the final complex to enforce productive, compartment-specific assembly (graham2003structureandassembly pages 9-11, wang2023structuralbasisof pages 1-2).

1.2 Definition: Vma22p as a dedicated ER assembly factor

Vma22p is defined experimentally as a non-subunit assembly factor required for biogenesis of functional V-ATPase. It is ER-associated, required for correct V0/V1 assembly and/or stability, and functions together with other ER assembly factors, especially Vma12p and Vma21p (hill1995vma22pisa pages 1-1, graham1998assemblyofthe pages 1-2, graham2003structureandassembly pages 9-11).

2) Molecular function of Vma22p

2.1 Core role: enabling V0 biogenesis by stabilizing/handling subunit a (Vph1p)

Loss of VMA22 causes failure to assemble functional V-ATPase and destabilization of the 100-kDa V0 subunit Vph1p (subunit a), with degradation occurring in the ER; meanwhile, multiple V1 subunits are produced at near-normal levels but fail to associate with vacuolar membranes (hill1995vma22pisa pages 3-4, hill1995vma22pisa pages 1-1).

Mechanistically, biochemical cross-linking and fractionation revealed that Vma12p and Vma22p form a stable assembly complex that directly interacts with Vph1p in the ER; the interaction is transient (reported half-life ~5 min), consistent with Vph1p transit through the ER during assembly/quality control rather than stable incorporation into the mature enzyme (graham1998assemblyofthe pages 1-2, graham1998assemblyofthe pages 9-10).

2.2 Assembly-factor complex: Vma12p/Vma22p heteromer

Vma22p is predicted to be hydrophilic and lacks transmembrane domains yet associates with ER membranes; this ER association depends on Vma12p, consistent with Vma12p serving as an ER membrane anchor/partner for Vma22p (graham1998assemblyofthe pages 3-4, graham2003structureandassembly pages 8-9).

3) Subcellular localization and interaction partners

3.1 Localization: ER-associated peripheral factor

Immunofluorescence and biochemical fractionation support that Vma22p is ER-associated with perinuclear/ER staining; association is saturable (increased cytosolic signal upon overproduction), reinforcing that membrane association likely occurs via protein–protein interactions rather than an intrinsic transmembrane helix (hill1995vma22pisa pages 5-6).

3.2 Protein interaction network in the assembly pathway

Evidence-supported interaction relationships include:
- Vma22p ↔ Vma12p: stable ER “assembly complex” (graham1998assemblyofthe pages 1-2, graham1998assemblyofthe pages 9-10).
- Vma12p/Vma22p ↔ Vph1p (V0 subunit a): direct, transient interaction in ER, stabilizing Vph1p and enabling V0 assembly and ER exit (graham1998assemblyofthe pages 1-2, graham1998assemblyofthe pages 9-10).
- Functional coordination with Vma21p: Vma21p is an ER cycling factor with a COPI-dependent ER retrieval motif; it is not part of the Vma12–Vma22 complex but participates in later/parallel steps including escorting assembled V0 intermediates and being recycled (graham2003structureandassembly pages 9-11, graham1999assemblyofthe pages 7-8).

4) Phenotypes of VMA22 loss-of-function (what breaks and how it is measured)

4.1 Canonical “Vma−” phenotypes linked to loss of vacuolar acidification

vma22 mutants show hallmark V-ATPase-defective phenotypes including defective vacuolar acidification (loss of quinacrine accumulation), pH sensitivity, slow growth, inability to grow on non-fermentable carbon sources, and calcium sensitivity (e.g., 100 mM CaCl2) (hill1995vma22pisa pages 2-3).

4.2 Cellular assembly phenotype: V1 in cytosol, V0 a-subunit absent from vacuolar membranes

In vma22Δ cells, V1 sector subunits fail to associate with vacuolar membranes and instead localize to the cytosol; Vph1p is strongly reduced in whole-cell extracts and absent from vacuolar membranes (hill1995vma22pisa pages 3-4).

5) Quantitative statistics and data points from key studies

Key quantitative measurements supporting functional annotation include:
- V-ATPase enzymatic activity (vacuolar membranes): wild type 7.0 vs 0.034 mmol ATP hydrolyzed/min/mg protein in vma22Δ, demonstrating near-complete loss of V-ATPase activity (published 1995-09, J Biol Chem, https://doi.org/10.1074/jbc.270.38.22329) (hill1995vma22pisa pages 2-3).
- ER quality control / stability of Vph1p: Vph1p half-life ~23 min in vma22Δ versus >400 min in wild type (and in ER-exit-blocked sec12 conditions), indicating failure to assemble triggers rapid ER turnover (hill1995vma22pisa pages 5-6).
- Transient ER assembly interaction: Vma12p/Vma22p–Vph1p interaction half-life ~5 min, consistent with a chaperone-like assembly step (graham1998assemblyofthe pages 1-2).

A consolidated evidence table is provided below.

Aspect	Key findings	Evidence/assay type	Publication (authors, year, journal)	URL/DOI	PaperQA citation id
Identity	• VMA22 corresponds to yeast ORF YHR060W and encodes Vma22p, a 181-aa ~21 kDa hydrophilic protein. • Functionally defined as a non-subunit V-ATPase assembly factor, not part of the mature enzyme complex.	Gene cloning/sequencing, complementation, immunoblotting	Hill & Stevens, 1995, J. Biol. Chem.	https://doi.org/10.1074/jbc.270.38.22329	(hill1995vma22pisa pages 3-4, hill1995vma22pisa pages 1-1)
Localization	• Vma22p is ER-associated despite lacking a signal peptide or transmembrane helix. • In wild type, immunofluorescence shows ER/perinuclear staining; membrane association depends on Vma12p.	Indirect immunofluorescence, subcellular fractionation, protease protection	Hill & Stevens, 1995, J. Biol. Chem.; Graham et al., 1998, J. Cell Biol.	https://doi.org/10.1074/jbc.270.38.22329; https://doi.org/10.1083/jcb.142.1.39	(hill1995vma22pisa pages 5-6, graham1998assemblyofthe pages 1-2, graham1998assemblyofthe pages 3-4)
Complex/partners	• Vma22p forms a stable membrane-associated Vma12p/Vma22p assembly complex. • This complex interacts directly and transiently with Vph1p (V0 a-subunit, 100 kDa); in 2023 structures Vma22 also contacts Vma12p, subunit d, and subunit F.	Chemical cross-linking, density-gradient fractionation, cryo-EM	Graham et al., 1998, J. Cell Biol.; Wang et al., 2023, PNAS	https://doi.org/10.1083/jcb.142.1.39; https://doi.org/10.1073/pnas.2217181120	(graham1998assemblyofthe pages 1-2, wang2023structuralbasisof pages 3-4, wang2023structuralbasisof pages 2-3)
Role in assembly	• Loss of VMA22 prevents proper V-ATPase assembly: V1 subunits accumulate in the cytosol and fail to associate with vacuolar membranes, while Vph1p becomes unstable/degraded. • Current model: Vma12–Vma22 acts as a heterodimeric ER chaperone/scaffold that recruits/stabilizes V0-region subunits and helps prevent premature V1 binding.	Vacuolar membrane biochemistry, Western blotting, immunolocalization, cryo-EM structural analysis	Hill & Stevens, 1995, J. Biol. Chem.; Wang et al., 2023, PNAS	https://doi.org/10.1074/jbc.270.38.22329; https://doi.org/10.1073/pnas.2217181120	(hill1995vma22pisa pages 3-4, hill1995vma22pisa pages 1-1, wang2023structuralbasisof pages 1-2, wang2023structuralbasisof pages 5-6)
Phenotypes	• vma22Δ/vma22 mutants show classic Vma− phenotypes: loss of quinacrine accumulation (defective vacuolar acidification), pH sensitivity, slow growth, failure on non-fermentable carbon sources, and sensitivity to 100 mM CaCl2. • Deletion gives near-normal levels of several V1 subunits in whole-cell extracts but loss of assembled enzyme on vacuolar membranes.	Growth phenotyping, quinacrine staining, vacuolar membrane assays, Western blotting	Hill & Stevens, 1995, J. Biol. Chem.	https://doi.org/10.1074/jbc.270.38.22329	(hill1995vma22pisa pages 2-3, hill1995vma22pisa pages 3-4)
Quantitative data	• Vacuolar membrane V-ATPase specific activity: 7.0 vs 0.034 mmol ATP/min/mg protein in wild type vs vma22Δ. • Vph1p half-life: ~23 min in vma22Δ vs >400 min in wild type/sec12; Vma12p/Vma22p–Vph1p interaction half-life ~5 min during ER transit.	Enzyme activity assay, pulse-chase/turnover analysis, cross-linking kinetics	Hill & Stevens, 1995, J. Biol. Chem.; Graham et al., 1998, J. Cell Biol.	https://doi.org/10.1074/jbc.270.38.22329; https://doi.org/10.1083/jcb.142.1.39	(hill1995vma22pisa pages 2-3, hill1995vma22pisa pages 5-6, graham1998assemblyofthe pages 1-2)
Recent structural insights	• Cryo-EM resolved V0 assembly intermediates bound to Vma12–Vma22 at 2.6–6.1 Å, with deposited models PDB 8EAS and 8EAT. • Vma22 shows fold mimicry of V-ATPase subunit D and occupies the d-subunit interface, providing a structural basis for blocking premature V1 binding; reported 18% similarity / 10% identity to subunit D.	Cryo-EM, atomic modeling, structural comparison	Wang et al., 2023, PNAS	https://doi.org/10.1073/pnas.2217181120	(wang2023structuralbasisof pages 1-2, wang2023structuralbasisof pages 2-3, wang2023structuralbasisof pages 8-8)

Table: This table summarizes core functional annotation evidence for Saccharomyces cerevisiae Vma22 from foundational and recent structural studies. It links identity, localization, assembly role, phenotypes, and quantitative measurements to specific experiments and citation IDs.

6) Recent developments (prioritizing 2023–2024)

6.1 2023 cryo-EM: structural mechanism for Vma22-mediated quality control and V0 templating

Wang et al. (2023-02, PNAS, https://doi.org/10.1073/pnas.2217181120) resolved cryo-EM structures of yeast V0 assembly intermediates bound to ER assembly factors Vma12p, Vma21p, and Vma22p. They show that the Vma12–Vma22 complex directly recruits V0 subunits (including recruitment/stabilization of subunit a onto the rotor ring) while blocking premature V1 association, providing a structural basis for preventing ER acidification (wang2023structuralbasisof pages 1-2, wang2023structuralbasisof pages 2-3).

Notable, reportable technical/quantitative details include map/model resolutions 2.6–6.1 Å and deposited structures PDB 8EAS/8EAT (wang2023structuralbasisof pages 1-2). Vma22p is reported to mimic the fold of V-ATPase subunit D (18% similarity, 10% identity) and occupy the binding site on subunit d that subunit D would otherwise use, explaining steric blockade of V1 binding during ER-stage assembly (wang2023structuralbasisof pages 2-3).

Two extracted figure regions from Wang et al. illustrate (i) a V0Δaef:Vma12-22p assembly intermediate and (ii) a schematic model of V0 assembly/quality control (wang2023structuralbasisof media 76e33002, wang2023structuralbasisof media c7199d37).

6.2 2024 cell biology: V-ATPase integrity as an autophagy-regulatory input (yeast as a modeling platform)

While not centered on Vma22 specifically, Lei et al. (2024-11, Molecular Biology of the Cell, https://doi.org/10.1091/mbc.e24-04-0189) reinforces current framing that ER-stage V0 assembly depends on core factors including Vma12, Vma21, and the peripheral membrane protein Vma22 (lei2024big1isa pages 1-2). In the same work, yeast genetics and vacuolar assays are used to model how impairment of a V-ATPase integrity factor (Big1/ATP6AP1-like) reduces vacuolar V-ATPase subunit levels and decreases bafilomycin A1–sensitive V-ATPase activity, linking assembly/integrity defects to downstream autophagy regulation even under conditions where TOR appears active (lei2024big1isa pages 2-4, lei2024big1isa pages 6-7).

7) Current applications and real-world implementations

7.1 Industrial/bioprocess relevance: fermentation performance is sensitive to vacuolar acidification capacity

V-ATPase function is directly connected to high-sugar fermentation outcomes. In a wine-like high sugar medium (200 g/L sugar; pH 3.5), Nguyen et al. (2018-04, Food Microbiology, https://doi.org/10.1016/j.fm.2017.09.021) found enrichment of vacuolar acidification genes among “fermentation essential genes,” including V-ATPase components and specifically noting that VMA22 (and VPH2) are involved in assembly (nguyen2018appropriatevacuolaracidification pages 16-20). Pharmacologic inhibition of V-ATPase using concanamycin A (300 nM) protracted fermentation from 167 h to 350 h and reduced viability relative to control, showing that reduced vacuolar acidification capacity can substantially slow industrially relevant fermentations (nguyen2018appropriatevacuolaracidification pages 8-12).

This provides a practical use-case for VMA22 functional annotation: engineering or screening for vacuolar acidification robustness (including assembly factor function) can be directly relevant to fermentation robustness under high sugar/ethanol/low pH stress (nguyen2018appropriatevacuolaracidification pages 12-16).

7.2 Translational/comparative application: yeast as a mechanistic testbed for conserved V-ATPase assembly logic

Recent studies explicitly use yeast to model V-ATPase assembly/integrity factors implicated in human biology, because yeast provides tractable genetics and conserved V0 assembly in the ER. Lei et al. demonstrate cross-species functional modeling by testing human ATP6AP1-related hypotheses in yeast and quantifying V-ATPase function and autophagy outputs, exemplifying how yeast assembly pathways (which include Vma22) inform eukaryotic cell biology more broadly (lei2024big1isa pages 1-2, lei2024big1isa pages 2-4).

8) Expert opinions and synthesis from authoritative sources

A widely cited expert review by Graham et al. (2003-04, Journal of Bioenergetics and Biomembranes, https://doi.org/10.1023/a:1025772730586) articulates a coherent assembly model in which Vma12p, Vma21p, and Vma22p are dedicated ER assembly factors required specifically for V0 formation and ER quality control. The review emphasizes that unassembled subunit a (Vph1p/Stv1p) undergoes ER quality control and turnover, while Vma21p cycles via an ER retrieval motif to escort assembled V0 intermediates (graham2003structureandassembly pages 8-9, graham2003structureandassembly pages 9-11). The 2023 cryo-EM work provides the structural mechanism underlying several of these review-era concepts (quality control; preventing premature V1 binding; templating V0 maturation) (wang2023structuralbasisof pages 1-2, wang2023structuralbasisof pages 2-3).

9) Summary functional annotation (concise)

VMA22 (P38784/YHR060W) encodes Vma22p, an ER-associated peripheral assembly factor required for V-ATPase V0-region biogenesis. Vma22p forms a stable complex with Vma12p that transiently binds and stabilizes Vph1p (V0 subunit a) during ER-stage assembly; loss of VMA22 causes rapid Vph1p turnover, cytosolic accumulation of V1 subunits, and near-complete loss of vacuolar V-ATPase activity and vacuolar acidification, producing canonical Vma− growth phenotypes (hill1995vma22pisa pages 1-1, graham1998assemblyofthe pages 1-2, hill1995vma22pisa pages 2-3). Recent cryo-EM structures show Vma22p blocks premature V1 binding by mimicking a V1 subunit interface (subunit D-like fold) while coordinating V0 intermediate maturation, providing a current mechanistic basis for its chaperone/quality-control role (wang2023structuralbasisof pages 2-3, wang2023structuralbasisof media c7199d37).

References

(hill1995vma22pisa pages 1-1): Kathryn J. Hill and Tom H. Stevens. Vma22p is a novel endoplasmic reticulum-associated protein required for assembly of the yeast vacuolar h+-atpase complex (*). The Journal of Biological Chemistry, 270:22329-22336, Sep 1995. URL: https://doi.org/10.1074/jbc.270.38.22329, doi:10.1074/jbc.270.38.22329. This article has 86 citations.
(graham1998assemblyofthe pages 1-2): Laurie A. Graham, Kathryn J. Hill, and Tom H. Stevens. Assembly of the yeast vacuolar h+-atpase occurs in the endoplasmic reticulum and requires a vma12p/vma22p assembly complex. The Journal of Cell Biology, 142:39-49, Jul 1998. URL: https://doi.org/10.1083/jcb.142.1.39, doi:10.1083/jcb.142.1.39. This article has 134 citations.
(wang2023structuralbasisof pages 1-2): Hanlin Wang, Stephanie A. Bueler, and John L. Rubinstein. Structural basis of v-atpase v _o region assembly by vma12p, 21p, and 22p. Proceedings of the National Academy of Sciences, Feb 2023. URL: https://doi.org/10.1073/pnas.2217181120, doi:10.1073/pnas.2217181120. This article has 18 citations and is from a highest quality peer-reviewed journal.
(graham2003structureandassembly pages 9-11): Laurie A. Graham, Andrew R. Flannery, and Tom H. Stevens. Structure and assembly of the yeast v-atpase. Journal of Bioenergetics and Biomembranes, 35:301-312, Apr 2003. URL: https://doi.org/10.1023/a:1025772730586, doi:10.1023/a:1025772730586. This article has 133 citations and is from a peer-reviewed journal.
(hill1995vma22pisa pages 3-4): Kathryn J. Hill and Tom H. Stevens. Vma22p is a novel endoplasmic reticulum-associated protein required for assembly of the yeast vacuolar h+-atpase complex (*). The Journal of Biological Chemistry, 270:22329-22336, Sep 1995. URL: https://doi.org/10.1074/jbc.270.38.22329, doi:10.1074/jbc.270.38.22329. This article has 86 citations.
(graham1998assemblyofthe pages 9-10): Laurie A. Graham, Kathryn J. Hill, and Tom H. Stevens. Assembly of the yeast vacuolar h+-atpase occurs in the endoplasmic reticulum and requires a vma12p/vma22p assembly complex. The Journal of Cell Biology, 142:39-49, Jul 1998. URL: https://doi.org/10.1083/jcb.142.1.39, doi:10.1083/jcb.142.1.39. This article has 134 citations.
(graham1998assemblyofthe pages 3-4): Laurie A. Graham, Kathryn J. Hill, and Tom H. Stevens. Assembly of the yeast vacuolar h+-atpase occurs in the endoplasmic reticulum and requires a vma12p/vma22p assembly complex. The Journal of Cell Biology, 142:39-49, Jul 1998. URL: https://doi.org/10.1083/jcb.142.1.39, doi:10.1083/jcb.142.1.39. This article has 134 citations.
(graham2003structureandassembly pages 8-9): Laurie A. Graham, Andrew R. Flannery, and Tom H. Stevens. Structure and assembly of the yeast v-atpase. Journal of Bioenergetics and Biomembranes, 35:301-312, Apr 2003. URL: https://doi.org/10.1023/a:1025772730586, doi:10.1023/a:1025772730586. This article has 133 citations and is from a peer-reviewed journal.
(hill1995vma22pisa pages 5-6): Kathryn J. Hill and Tom H. Stevens. Vma22p is a novel endoplasmic reticulum-associated protein required for assembly of the yeast vacuolar h+-atpase complex (*). The Journal of Biological Chemistry, 270:22329-22336, Sep 1995. URL: https://doi.org/10.1074/jbc.270.38.22329, doi:10.1074/jbc.270.38.22329. This article has 86 citations.
(graham1999assemblyofthe pages 7-8): LA Graham and TH Stevens. Assembly of the yeast vacuolar proton-translocating atpase. Journal of Bioenergetics and Biomembranes, 31:39-47, Feb 1999. URL: https://doi.org/10.1023/a:1005455411918, doi:10.1023/a:1005455411918. This article has 41 citations and is from a peer-reviewed journal.
(hill1995vma22pisa pages 2-3): Kathryn J. Hill and Tom H. Stevens. Vma22p is a novel endoplasmic reticulum-associated protein required for assembly of the yeast vacuolar h+-atpase complex (*). The Journal of Biological Chemistry, 270:22329-22336, Sep 1995. URL: https://doi.org/10.1074/jbc.270.38.22329, doi:10.1074/jbc.270.38.22329. This article has 86 citations.
(wang2023structuralbasisof pages 3-4): Hanlin Wang, Stephanie A. Bueler, and John L. Rubinstein. Structural basis of v-atpase v _o region assembly by vma12p, 21p, and 22p. Proceedings of the National Academy of Sciences, Feb 2023. URL: https://doi.org/10.1073/pnas.2217181120, doi:10.1073/pnas.2217181120. This article has 18 citations and is from a highest quality peer-reviewed journal.
(wang2023structuralbasisof pages 2-3): Hanlin Wang, Stephanie A. Bueler, and John L. Rubinstein. Structural basis of v-atpase v _o region assembly by vma12p, 21p, and 22p. Proceedings of the National Academy of Sciences, Feb 2023. URL: https://doi.org/10.1073/pnas.2217181120, doi:10.1073/pnas.2217181120. This article has 18 citations and is from a highest quality peer-reviewed journal.
(wang2023structuralbasisof pages 5-6): Hanlin Wang, Stephanie A. Bueler, and John L. Rubinstein. Structural basis of v-atpase v _o region assembly by vma12p, 21p, and 22p. Proceedings of the National Academy of Sciences, Feb 2023. URL: https://doi.org/10.1073/pnas.2217181120, doi:10.1073/pnas.2217181120. This article has 18 citations and is from a highest quality peer-reviewed journal.
(wang2023structuralbasisof pages 8-8): Hanlin Wang, Stephanie A. Bueler, and John L. Rubinstein. Structural basis of v-atpase v _o region assembly by vma12p, 21p, and 22p. Proceedings of the National Academy of Sciences, Feb 2023. URL: https://doi.org/10.1073/pnas.2217181120, doi:10.1073/pnas.2217181120. This article has 18 citations and is from a highest quality peer-reviewed journal.
(wang2023structuralbasisof media 76e33002): Hanlin Wang, Stephanie A. Bueler, and John L. Rubinstein. Structural basis of v-atpase v _o region assembly by vma12p, 21p, and 22p. Proceedings of the National Academy of Sciences, Feb 2023. URL: https://doi.org/10.1073/pnas.2217181120, doi:10.1073/pnas.2217181120. This article has 18 citations and is from a highest quality peer-reviewed journal.
(wang2023structuralbasisof media c7199d37): Hanlin Wang, Stephanie A. Bueler, and John L. Rubinstein. Structural basis of v-atpase v _o region assembly by vma12p, 21p, and 22p. Proceedings of the National Academy of Sciences, Feb 2023. URL: https://doi.org/10.1073/pnas.2217181120, doi:10.1073/pnas.2217181120. This article has 18 citations and is from a highest quality peer-reviewed journal.
(lei2024big1isa pages 1-2): Yuchen Lei, Ying Yang, Zhihai Zhang, Ruoxi Zhang, Xinxin Song, Sami N. Malek, Daolin Tang, and Daniel J. Klionsky. Big1 is a newly identified autophagy regulator that is critical for a fully functional v-atpase. Molecular Biology of the Cell, Nov 2024. URL: https://doi.org/10.1091/mbc.e24-04-0189, doi:10.1091/mbc.e24-04-0189. This article has 2 citations and is from a domain leading peer-reviewed journal.
(lei2024big1isa pages 2-4): Yuchen Lei, Ying Yang, Zhihai Zhang, Ruoxi Zhang, Xinxin Song, Sami N. Malek, Daolin Tang, and Daniel J. Klionsky. Big1 is a newly identified autophagy regulator that is critical for a fully functional v-atpase. Molecular Biology of the Cell, Nov 2024. URL: https://doi.org/10.1091/mbc.e24-04-0189, doi:10.1091/mbc.e24-04-0189. This article has 2 citations and is from a domain leading peer-reviewed journal.
(lei2024big1isa pages 6-7): Yuchen Lei, Ying Yang, Zhihai Zhang, Ruoxi Zhang, Xinxin Song, Sami N. Malek, Daolin Tang, and Daniel J. Klionsky. Big1 is a newly identified autophagy regulator that is critical for a fully functional v-atpase. Molecular Biology of the Cell, Nov 2024. URL: https://doi.org/10.1091/mbc.e24-04-0189, doi:10.1091/mbc.e24-04-0189. This article has 2 citations and is from a domain leading peer-reviewed journal.
(nguyen2018appropriatevacuolaracidification pages 16-20): Trung D. Nguyen, Michelle E. Walker, Jennifer M. Gardner, and Vladimir Jiranek. Appropriate vacuolar acidification in saccharomyces cerevisiae is associated with efficient high sugar fermentation. Food microbiology, 70:262-268, Apr 2018. URL: https://doi.org/10.1016/j.fm.2017.09.021, doi:10.1016/j.fm.2017.09.021. This article has 8 citations and is from a domain leading peer-reviewed journal.
(nguyen2018appropriatevacuolaracidification pages 8-12): Trung D. Nguyen, Michelle E. Walker, Jennifer M. Gardner, and Vladimir Jiranek. Appropriate vacuolar acidification in saccharomyces cerevisiae is associated with efficient high sugar fermentation. Food microbiology, 70:262-268, Apr 2018. URL: https://doi.org/10.1016/j.fm.2017.09.021, doi:10.1016/j.fm.2017.09.021. This article has 8 citations and is from a domain leading peer-reviewed journal.
(nguyen2018appropriatevacuolaracidification pages 12-16): Trung D. Nguyen, Michelle E. Walker, Jennifer M. Gardner, and Vladimir Jiranek. Appropriate vacuolar acidification in saccharomyces cerevisiae is associated with efficient high sugar fermentation. Food microbiology, 70:262-268, Apr 2018. URL: https://doi.org/10.1016/j.fm.2017.09.021, doi:10.1016/j.fm.2017.09.021. This article has 8 citations and is from a domain leading peer-reviewed journal.

Citations

graham1998assemblyofthe pages 1-2
wang2023structuralbasisof pages 1-2
wang2023structuralbasisof pages 2-3
nguyen2018appropriatevacuolaracidification pages 16-20
nguyen2018appropriatevacuolaracidification pages 8-12
nguyen2018appropriatevacuolaracidification pages 12-16
graham2003structureandassembly pages 9-11
graham1998assemblyofthe pages 9-10
graham1998assemblyofthe pages 3-4
graham2003structureandassembly pages 8-9
graham1999assemblyofthe pages 7-8
wang2023structuralbasisof pages 3-4
wang2023structuralbasisof pages 5-6
wang2023structuralbasisof pages 8-8
https://doi.org/10.1074/jbc.270.38.22329
https://doi.org/10.1083/jcb.142.1.39;
https://doi.org/10.1073/pnas.2217181120
https://doi.org/10.1074/jbc.270.38.22329;
https://doi.org/10.1083/jcb.142.1.39
https://doi.org/10.1091/mbc.e24-04-0189
https://doi.org/10.1016/j.fm.2017.09.021
https://doi.org/10.1023/a:1025772730586
https://doi.org/10.1074/jbc.270.38.22329,
https://doi.org/10.1083/jcb.142.1.39,
https://doi.org/10.1073/pnas.2217181120,
https://doi.org/10.1023/a:1025772730586,
https://doi.org/10.1023/a:1005455411918,
https://doi.org/10.1091/mbc.e24-04-0189,
https://doi.org/10.1016/j.fm.2017.09.021,

📄 View Raw YAML

id: P38784
gene_symbol: VMA22
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:559292
  label: Saccharomyces cerevisiae
description: >-
  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. The "unfolded protein binding" annotations overgeneralize this
  specific assembly-factor role.
alternative_products:
- name: "1"
  id: P38784-1
- name: "2"
  id: P38784-2
  sequence_note: VSP_058123
existing_annotations:
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      The PANTHER/IBA unfolded protein binding annotation reflects transfer from
      assembly-factor biology but overstates Vma22 as a general unfolded-protein
      binding chaperone.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Vma22 acts in a dedicated Vma12-Vma22 ER assembly complex for the V-ATPase
      V0 sector. The evidence supports specific assembly-intermediate binding,
      not broad unfolded protein binding.
    supported_by:
    - reference_id: PMID:9660861
      supporting_text: >-
        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.
    - reference_id: file:yeast/VMA22/VMA22-deep-research-falcon.md
      supporting_text: >-
        **VMA22 (P38784/YHR060W)** encodes **Vma22p**, an **ER-associated
        peripheral assembly factor** required for **V-ATPase V0-region
        biogenesis**.
- term:
    id: GO:1990871
    label: Vma12-Vma22 assembly complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    reason: >-
      Vma12-Vma22 complex membership is a core feature of Vma22 function and is
      supported by both family-transfer and direct experimental evidence.
    supported_by:
    - reference_id: PMID:9660861
      supporting_text: >-
        Vma12p and Vma22p form a stable membrane associated complex.
- term:
    id: GO:0070072
    label: vacuolar proton-transporting V-type ATPase complex assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      InterPro transfer to V-ATPase complex assembly is consistent with direct
      yeast genetic and biochemical evidence for Vma22.
    action: ACCEPT
    reason: >-
      Although this particular annotation is electronic, it matches the
      experimentally demonstrated core role of Vma22 in V-ATPase assembly.
    supported_by:
    - reference_id: PMID:7673216
      supporting_text: >-
        vma22 delta cells contain no V-ATPase activity due to a failure to
        assemble the enzyme complex.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:26928762
  review:
    summary: >-
      The nucleus annotation is from a high-throughput localization resource and
      conflicts with focused biochemical evidence that Vma22 is ER-associated.
    action: REMOVE
    reason: >-
      Vma22's established function is in the ER-localized Vma12-Vma22 assembly
      complex. No gene-specific evidence supports nuclear localization as a site
      of Vma22 function.
    supported_by:
    - reference_id: PMID:7673216
      supporting_text: >-
        Vma22p is a 21-kDa hydrophilic protein that is not a subunit of the
        V-ATPase but rather is associated with ER membranes.
- term:
    id: GO:1990871
    label: Vma12-Vma22 assembly complex
  evidence_type: IPI
  original_reference_id: PMID:9660861
  review:
    summary: >-
      Direct interaction and cofractionation evidence supports Vma22 as part of
      the Vma12-Vma22 assembly complex.
    action: ACCEPT
    reason: >-
      This is a precise cellular-component/complex annotation for Vma22's core
      assembly-factor role.
    supported_by:
    - reference_id: PMID:9660861
      supporting_text: >-
        Vma12p and Vma22p were found to interact directly as determined by
        chemical cross-linking analysis and cofractionation under conditions of
        gentle detergent solubilization.
- term:
    id: GO:0007035
    label: vacuolar acidification
  evidence_type: IMP
  original_reference_id: PMID:1628805
  review:
    summary: >-
      VMA22 was identified among VPH/VMA genes required for vacuolar acidity.
      The phenotype is a downstream consequence of failed V-ATPase assembly.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:1628805
      supporting_text: >-
        Thirty nine vacuolar pH (Vph-) mutants were identified.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IMP
  original_reference_id: PMID:7673216
  review:
    summary: >-
      The 1995 Vma22 paper supports a V-ATPase assembly factor role, not generic
      unfolded protein binding.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Vma22 is ER-associated and required for V-ATPase assembly, but the evidence
      does not show broad binding to unfolded proteins. The assembly process and
      Vma12-Vma22 complex annotations capture the biology more accurately.
    supported_by:
    - reference_id: PMID:7673216
      supporting_text: >-
        Vma22p is a 21-kDa hydrophilic protein that is not a subunit of the
        V-ATPase but rather is associated with ER membranes.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IMP
  original_reference_id: PMID:8582630
  review:
    summary: >-
      VPH6/VMA22 mutant phenotypes support defective V-ATPase assembly rather
      than a standalone unfolded-protein binding activity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This annotation generalizes a specific assembly-factor defect into a broad
      chaperone-like molecular function. V-ATPase complex assembly is the
      defensible process annotation.
    supported_by:
    - reference_id: PMID:8582630
      supporting_text: >-
        vph6 mutant strains fail to assemble the vacuolar H(+)-ATPase
        (V-ATPase).
- term:
    id: GO:0070072
    label: vacuolar proton-transporting V-type ATPase complex assembly
  evidence_type: IMP
  original_reference_id: PMID:7673216
  review:
    summary: >-
      Vma22 is required for V-ATPase complex assembly; vma22 deletion eliminates
      V-ATPase activity because the enzyme complex fails to assemble.
    action: ACCEPT
    reason: >-
      This is the central experimentally supported biological process for Vma22.
    supported_by:
    - reference_id: PMID:7673216
      supporting_text: >-
        vma22 delta cells contain no V-ATPase activity due to a failure to
        assemble the enzyme complex.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  review:
    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.
    action: NEW
    reason: >-
      Existing GOA contains a misleading 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.
    supported_by:
    - reference_id: PMID:7673216
      supporting_text: >-
        Vma22p is a 21-kDa hydrophilic protein that is not a subunit of the
        V-ATPase but rather is associated with ER membranes.
    - reference_id: PMID:9660861
      supporting_text: >-
        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.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings:
  - statement: >-
      VMA22 IBA annotations derive from family-transfer context and are strongest
      for Vma12-Vma22 complex membership; unfolded protein binding is too broad.
    supporting_text: >-
      GOA WITH/FROM includes PANTHER evidence for GO:1990871 Vma12-Vma22
      assembly complex and GO:0051082 unfolded protein binding.
- id: UniProt:P38784
  title: UniProtKB entry for VMA22_YEAST
  findings:
  - statement: >-
      Vma22 is required for V-ATPase activity and has two UniProt alternative
      initiation isoforms.
    supporting_text: >-
      FUNCTION: Required for V-ATPase activity. ALTERNATIVE PRODUCTS: Event =
      Alternative initiation; Named isoforms = 2.
- id: PMID:1628805
  title: Genes required for vacuolar acidity in Saccharomyces cerevisiae
  findings:
  - statement: >-
      VPH/VMA mutants identify genes required for vacuolar acidity.
    supporting_text: >-
      Thirty nine vacuolar pH (Vph-) mutants were identified.
- id: PMID:26928762
  title: >-
    One library to make them all: streamlining the creation of yeast libraries
    via a SWAp-Tag strategy
  findings: []
- id: PMID:7673216
  title: >-
    Vma22p is a novel endoplasmic reticulum-associated protein required for
    assembly of the yeast vacuolar H(+)-ATPase complex
  findings:
  - statement: >-
      Vma22 is ER-associated and required for V-ATPase assembly but is not a
      subunit of the mature V-ATPase.
    supporting_text: >-
      Vma22p is a 21-kDa hydrophilic protein that is not a subunit of the
      V-ATPase but rather is associated with ER membranes.
  - statement: >-
      Loss of VMA22 blocks V-ATPase complex assembly and activity.
    supporting_text: >-
      vma22 delta cells contain no V-ATPase activity due to a failure to assemble
      the enzyme complex.
- id: PMID:8582630
  title: >-
    vph6 mutants of Saccharomyces cerevisiae require calcineurin for growth and
    are defective in vacuolar H(+)-ATPase assembly
  findings:
  - statement: >-
      VPH6/VMA22 mutants fail to assemble the V-ATPase.
    supporting_text: >-
      vph6 mutant strains fail to assemble the vacuolar H(+)-ATPase (V-ATPase).
- id: PMID:9660861
  title: >-
    Assembly of the yeast vacuolar H+-ATPase occurs in the endoplasmic reticulum
    and requires a Vma12p/Vma22p assembly complex
  findings:
  - statement: >-
      Vma12 and Vma22 form a stable ER-associated complex that transiently
      interacts with Vph1 during V-ATPase assembly.
    supporting_text: >-
      Vma12p and Vma22p form a stable membrane associated complex. Cross-linking
      analysis also revealed a direct physical interaction between the
      Vma12p/Vma22p assembly complex and Vph1p.
  - statement: >-
      Vma22 is a dedicated assembly factor, not a general molecular chaperone.
    supporting_text: >-
      Unlike general molecular chaperones such as Kar2p/BiP, Vma12p, Vma21p,
      and Vma22p represent a class of ER resident proteins dedicated to the
      assembly of a specific enzyme complex, the V-ATPase.
- id: file:yeast/VMA22/VMA22-deep-research-falcon.md
  title: Falcon deep research report for VMA22
  findings:
  - statement: >-
      Falcon supports Vma22 as an ER-associated V-ATPase V0-region assembly
      factor and not a general unfolded-protein binding protein.
    supporting_text: >-
      VMA22 encodes Vma22p, an ER-associated peripheral assembly factor required
      for V-ATPase V0-region biogenesis. Vma22p forms a stable complex with
      Vma12p that transiently binds and stabilizes Vph1p during ER-stage
      assembly.
core_functions:
- description: >-
    Vma22 is a dedicated ER-associated V-ATPase assembly factor. In complex with
    Vma12, it transiently binds the Vph1/V0-sector assembly intermediate in the
    ER, stabilizing V0 assembly before the V-ATPase reaches the vacuole. Vma22 is
    therefore required for V-ATPase complex assembly and downstream vacuolar
    acidification, but it is not a mature V-ATPase subunit and should not be
    curated as a general unfolded-protein binding factor.
  directly_involved_in:
  - id: GO:0070072
    label: vacuolar proton-transporting V-type ATPase complex assembly
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  in_complex:
    id: GO:1990871
    label: Vma12-Vma22 assembly complex
  supported_by:
  - reference_id: PMID:7673216
    supporting_text: >-
      vma22 delta cells contain no V-ATPase activity due to a failure to assemble
      the enzyme complex.
  - reference_id: PMID:9660861
    supporting_text: >-
      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.
  - reference_id: file:yeast/VMA22/VMA22-deep-research-falcon.md
    supporting_text: >-
      VMA22 encodes Vma22p, an ER-associated peripheral assembly factor required
      for V-ATPase V0-region biogenesis. Vma22p forms a stable complex with
      Vma12p that transiently binds and stabilizes Vph1p during ER-stage
      assembly.
proposed_new_terms:
- proposed_name: V-ATPase V0 sector assembly factor activity
  proposed_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. QuickGO has no GO:0140557 term available, and generic protein
    folding chaperone terms would overstate Vma22 as a general foldase rather
    than a V-ATPase assembly factor.
suggested_questions:
- question: >-
    What is the precise structural interface by which the Vma12-Vma22 complex
    contacts Vph1 or other V0-sector assembly intermediates?
- question: >-
    Does Vma22 have any separable function outside the Vma12-Vma22 assembly
    complex, or is all detectable Vma22 activity complex-dependent?
- question: >-
    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?
suggested_experiments:
- description: >-
    Use structure-guided Vma22 mutants to disrupt Vma12 binding or Vph1
    interaction separately, then measure V0 assembly, Vph1 stability, and
    vacuolar acidification.
  experiment_type: genetics
- description: >-
    Reconstitute the Vma12-Vma22 complex with Vph1/V0 assembly intermediates and
    map transient contacts by crosslinking mass spectrometry or cryo-EM.
  experiment_type: biochemistry
- description: >-
    Test the UniProt alternative initiation isoforms for expression, ER membrane
    association, Vma12 binding, and complementation of vma22 deletion phenotypes.
  experiment_type: cell biology

VMA22

Gene Description

Proposed New Ontology Terms

V-ATPase V0 sector assembly factor activity

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Research report: Saccharomyces cerevisiae VMA22 (UniProt P38784; ORF YHR060W) — functional annotation

0) Target verification (critical disambiguation)

1) Key concepts and definitions (current understanding)

1.1 V-ATPase architecture and why assembly factors matter

1.2 Definition: Vma22p as a dedicated ER assembly factor

2) Molecular function of Vma22p

2.1 Core role: enabling V0 biogenesis by stabilizing/handling subunit a (Vph1p)

2.2 Assembly-factor complex: Vma12p/Vma22p heteromer

3) Subcellular localization and interaction partners

3.1 Localization: ER-associated peripheral factor

3.2 Protein interaction network in the assembly pathway

4) Phenotypes of VMA22 loss-of-function (what breaks and how it is measured)

4.1 Canonical “Vma−” phenotypes linked to loss of vacuolar acidification

4.2 Cellular assembly phenotype: V1 in cytosol, V0 a-subunit absent from vacuolar membranes

5) Quantitative statistics and data points from key studies

6) Recent developments (prioritizing 2023–2024)

6.1 2023 cryo-EM: structural mechanism for Vma22-mediated quality control and V0 templating

6.2 2024 cell biology: V-ATPase integrity as an autophagy-regulatory input (yeast as a modeling platform)

7) Current applications and real-world implementations

7.1 Industrial/bioprocess relevance: fermentation performance is sensitive to vacuolar acidification capacity

7.2 Translational/comparative application: yeast as a mechanistic testbed for conserved V-ATPase assembly logic

8) Expert opinions and synthesis from authoritative sources

9) Summary functional annotation (concise)

Citations

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