--- provider: falcon model: Edison Scientific Literature cached: false start_time: '2025-12-26T10:23:01.462298' end_time: '2025-12-26T10:27:10.157280' duration_seconds: 248.7 template_file: templates/gene_research_go_focused.md template_variables: organism: human gene_id: ATP6V0C gene_symbol: ATP6V0C uniprot_accession: P27449 protein_description: 'RecName: Full=V-type proton ATPase 16 kDa proteolipid subunit c {ECO:0000305}; Short=V-ATPase 16 kDa proteolipid subunit c {ECO:0000305}; AltName: Full=Vacuolar proton pump 16 kDa proteolipid subunit c {ECO:0000305};' gene_info: Name=ATP6V0C; Synonyms=ATP6C, ATP6L, ATPL; organism_full: Homo sapiens (Human). protein_family: Belongs to the V-ATPase proteolipid subunit family. protein_domains: ATPase_proteolipid_c-like_dom. (IPR002379); ATPase_proteolipid_csu. (IPR000245); ATPase_proteolipid_su_C_euk. (IPR011555); F/V-ATP_Csub_sf. (IPR035921); ATP-synt_C (PF00137) provider_config: timeout: 600 max_retries: 3 parameters: allowed_domains: [] temperature: 0.1 citation_count: 11 --- ## 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:** P27449 - **Protein Description:** RecName: Full=V-type proton ATPase 16 kDa proteolipid subunit c {ECO:0000305}; Short=V-ATPase 16 kDa proteolipid subunit c {ECO:0000305}; AltName: Full=Vacuolar proton pump 16 kDa proteolipid subunit c {ECO:0000305}; - **Gene Information:** Name=ATP6V0C; Synonyms=ATP6C, ATP6L, ATPL; - **Organism (full):** Homo sapiens (Human). - **Protein Family:** Belongs to the V-ATPase proteolipid subunit family. - **Key Domains:** ATPase_proteolipid_c-like_dom. (IPR002379); ATPase_proteolipid_csu. (IPR000245); ATPase_proteolipid_su_C_euk. (IPR011555); F/V-ATP_Csub_sf. (IPR035921); ATP-synt_C (PF00137) ### MANDATORY VERIFICATION STEPS: 1. **Check if the gene symbol "ATP6V0C" matches the protein description above** 2. **Verify the organism is correct:** Homo sapiens (Human). 3. **Check if protein family/domains align with what you find in literature** 4. **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 'ATP6V0C' 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 **ATP6V0C** (gene ID: ATP6V0C, UniProt: P27449) in human. 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:** P27449 - **Protein Description:** RecName: Full=V-type proton ATPase 16 kDa proteolipid subunit c {ECO:0000305}; Short=V-ATPase 16 kDa proteolipid subunit c {ECO:0000305}; AltName: Full=Vacuolar proton pump 16 kDa proteolipid subunit c {ECO:0000305}; - **Gene Information:** Name=ATP6V0C; Synonyms=ATP6C, ATP6L, ATPL; - **Organism (full):** Homo sapiens (Human). - **Protein Family:** Belongs to the V-ATPase proteolipid subunit family. - **Key Domains:** ATPase_proteolipid_c-like_dom. (IPR002379); ATPase_proteolipid_csu. (IPR000245); ATPase_proteolipid_su_C_euk. (IPR011555); F/V-ATP_Csub_sf. (IPR035921); ATP-synt_C (PF00137) ### MANDATORY VERIFICATION STEPS: 1. **Check if the gene symbol "ATP6V0C" matches the protein description above** 2. **Verify the organism is correct:** Homo sapiens (Human). 3. **Check if protein family/domains align with what you find in literature** 4. **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 'ATP6V0C' 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 **ATP6V0C** (gene ID: ATP6V0C, UniProt: P27449) in human. 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. Plan and approach We verified the gene/protein identity and then synthesized recent, authoritative evidence on ATP6V0C’s biochemical role in V‑ATPase, with emphasis on 2023–2024 literature, supported by foundational reviews for core mechanism and localization. Where detailed, quantitative or site‑specific claims were not directly supported by the retrieved sources, we constrained statements accordingly and cited only available context. Comprehensive research report: ATP6V0C (UniProt P27449) in human 1) Key concepts and definitions - Identity and family. ATP6V0C encodes the c proteolipid subunit of the membrane Vo sector of the V‑type H+‑ATPase (V‑ATPase) in Homo sapiens. The c subunit is an essential component of the proteolipid c‑ring that constitutes the rotary proton‑translocating element of the pump; it belongs to the V‑ATPase proteolipid subunit family and is highly hydrophobic with multiple transmembrane helices (four in subunit c; a c″ variant has five) (review and structural context) (eaton2021theh+atpase(vatpase) pages 1-5, indrawinata2023structuralandfunctional pages 5-6, indrawinata2023structuralandfunctional pages 4-5). URL (Eaton 2021): https://doi.org/10.1152/ajpcell.00442.2020 (Mar 2021). URL (Indrawinata 2023): https://doi.org/10.3389/fnmol.2023.1135015 (Jul 2023). - Structural role in the V‑ATPase. The c and c″ proteolipids assemble into a multi‑subunit c‑ring (often ~10 proteolipids with a ~9:1 c:c″ ratio) that rotates against subunit a during catalysis; essential glutamate on c (e.g., E139 in human c) cycles protonation/deprotonation to enable ion translocation (mechanistic summaries from recent structural analyses) (indrawinata2023structuralandfunctional pages 5-6, indrawinata2023structuralandfunctional pages 4-5). URL: https://doi.org/10.3389/fnmol.2023.1135015 (Jul 2023). 2) Biochemical function and current mechanistic understanding - Core reaction and coupling. The V‑ATPase hydrolyzes ATP in its V1 domain to drive rotary torque transmitted to the Vo sector, moving protons across the membrane via the c‑ring and the paired hemichannels in subunit a; typical coupling is approximately 10 H+ translocated per 3 ATP hydrolyzed (mechanistic review and structural mapping of the Vo interface and catalytic coupling) (indrawinata2023structuralandfunctional pages 4-5, indrawinata2023structuralandfunctional pages 5-6). URL: https://doi.org/10.3389/fnmol.2023.1135015 (Jul 2023). - Proton binding sites and pathway. In human c, a conserved glutamate (E139) binds and releases H+ as the ring rotates past subunit a’s hemichannels; proton release involves conserved arginine in subunit a and a luminal network at the a7–a8 helices, consistent with rotary proton pump models (indrawinata2023structuralandfunctional pages 5-6). URL: https://doi.org/10.3389/fnmol.2023.1135015 (Jul 2023). - Inhibitors. Classic small‑molecule V‑ATPase inhibitors (e.g., bafilomycin, concanamycin) inhibit V‑ATPase activity in cells and are widely used as pharmacologic probes; the reviews establish their use but without site‑specific binding details in the retrieved excerpts (eaton2021theh+atpase(vatpase) pages 1-5). URL: https://doi.org/10.1152/ajpcell.00442.2020 (Mar 2021). - Recent structural insights. Contemporary cryo‑EM work has further resolved the Vo interface and hemichannels, supporting the c‑ring mechanistic model and the a–c interactions underlying proton translocation; these 2023 analyses summarize human/yeast structural principles applicable to the human enzyme (indrawinata2023structuralandfunctional pages 4-5, indrawinata2023structuralandfunctional pages 5-6). URL: https://doi.org/10.3389/fnmol.2023.1135015 (Jul 2023). 3) Cellular localization and complex assembly - Organellar distribution. V‑ATPases are broadly present on intracellular organelles (endosomes, lysosomes, secretory vesicles, Golgi/ER intermediates), where they acidify lumens; in specialized cell types, V‑ATPase can localize to the plasma membrane to acidify the extracellular milieu (e.g., kidney intercalated cells, osteoclast ruffled border) (eaton2021theh+atpase(vatpase) pages 1-5). URL: https://doi.org/10.1152/ajpcell.00442.2020 (Mar 2021). - Assembly. V‑ATPase comprises V1 (ATP‑hydrolytic) and Vo (proton channel) sectors that associate reversibly; the Vo c‑ring (containing ATP6V0C) forms the rotary element contacting subunit a and the central rotor stalk from V1, while peripheral EG stalks act as stators (indrawinata2023structuralandfunctional pages 4-5, eaton2021theh+atpase(vatpase) pages 1-5). URL: https://doi.org/10.3389/fnmol.2023.1135015 (Jul 2023); https://doi.org/10.1152/ajpcell.00442.2020 (Mar 2021). 4) Pathway roles and regulatory axes - Lysosomal acidification and degradative flux. V‑ATPase‑driven acidification is essential for lysosomal hydrolase activity and endocytic/autophagic cargo degradation; compromised c‑ring function impairs these pathways (eaton2021theh+atpase(vatpase) pages 1-5). URL: https://doi.org/10.1152/ajpcell.00442.2020 (Mar 2021). - Nutrient sensing and mTORC1. V‑ATPase is a central hub at lysosomes linking acidification to mTORC1 nutrient sensing/signaling; the review positions the complex as a signaling scaffold beyond its pump activity (eaton2021theh+atpase(vatpase) pages 1-5). URL: https://doi.org/10.1152/ajpcell.00442.2020 (Mar 2021). - Autophagy-related regulation via V0c. Recent work implicates V0c in single‑membrane LC3 lipidation (CASM) through interactions with ATG16L1–ATG5‑12 and highlights Rabconnectin‑3 (Rogdi/RAV2‑like) as a V‑ATPase regulatory factor in metazoans; this places the c subunit in broader vesicle/autophagy control networks (winkley2025abstract2474rogdi pages 17-21). URL: https://doi.org/10.1016/j.jbc.2025.110002 (May 2025). 5) Disease associations and perturbations (human evidence) - Neurodevelopmental phenotypes from ATP6V0C variation. A 2024 review collating clinical genetics reports links heterozygous missense ATP6V0C variants and structural deletions with a syndromic neurodevelopmental spectrum including developmental delay, epilepsy (mean onset ~25 months), and brain MRI anomalies (corpus callosum/cerebellar vermis hypoplasia, delayed myelination). Cross‑species functional modeling (yeast, C. elegans, Drosophila) supports pathogenicity and implicates impaired Vo a–c interactions during catalysis (falace2024vatpasedysfunctionin pages 6-8). URL: https://doi.org/10.3390/cells13171441 (Aug 2024). - Essentiality and organismal physiology. Disrupting the proteolipid c‑ring is embryonic lethal in animal models, underscoring indispensability for organelle acidification and specialized plasma membrane acidification roles (kidney, bone, sensory tissues) (eaton2021theh+atpase(vatpase) pages 1-5). URL: https://doi.org/10.1152/ajpcell.00442.2020 (Mar 2021). 6) Applications and real‑world implementations - Pharmacological tools. Bafilomycin and concanamycin are widely used cellular probes to acutely inhibit V‑ATPase and interrogate acidification‑dependent trafficking, lysosomal degradation, and signaling; they remain standard tools across cell biology and disease models (eaton2021theh+atpase(vatpase) pages 1-5). URL: https://doi.org/10.1152/ajpcell.00442.2020 (Mar 2021). - Translational angles. The V‑ATPase is positioned as a therapeutic target in cancer, bone disease and viral entry/trafficking due to its roles in acidification and signaling; the c‑ring is the pump’s core rotor targeted by such pharmacology (high‑level review perspective) (eaton2021theh+atpase(vatpase) pages 1-5). URL: https://doi.org/10.1152/ajpcell.00442.2020 (Mar 2021). 7) Quantitative/statistical details extracted - Coupling stoichiometry. Approximate functional coupling reported as ~10 protons translocated per 3 ATP hydrolyzed in human V‑ATPase assemblies (mechanistic summary) (indrawinata2023structuralandfunctional pages 5-6). URL: https://doi.org/10.3389/fnmol.2023.1135015 (Jul 2023). - Genetic cohort features. In the collated ATP6V0C patient cohort, seizures were frequent with mean onset 24.6 ± 8.0 months; neuroimaging abnormalities included corpus callosum/cerebellar vermis hypoplasia and delayed myelination (falace2024vatpasedysfunctionin pages 6-8). URL: https://doi.org/10.3390/cells13171441 (Aug 2024). Expert analysis and synthesis - The human ATP6V0C product is the rotary proteolipid of the V‑ATPase Vo sector, forming the c‑ring that underlies proton transport. Structural work converges on a conserved glutamate‑based binding/release cycle at the c‑ring that interfaces with subunit a hemichannels to mediate vectorial H+ movement. This explains why ATP6V0C variation perturbs acidification‑dependent biology in neurons and across organ systems. The evidence base strongly supports lysosomal/endosomal roles and broader signaling functions (e.g., mTORC1), while recent reports expand regulatory interactions to autophagy machinery (ATG16L1) and assembly factors (Rabconnectin‑3), highlighting how the c‑ring can be a nexus for both transport and scaffolding depending on context (indrawinata2023structuralandfunctional pages 4-5, indrawinata2023structuralandfunctional pages 5-6, eaton2021theh+atpase(vatpase) pages 1-5, falace2024vatpasedysfunctionin pages 6-8, winkley2025abstract2474rogdi pages 17-21). URLs: https://doi.org/10.3389/fnmol.2023.1135015 (Jul 2023); https://doi.org/10.1152/ajpcell.00442.2020 (Mar 2021); https://doi.org/10.3390/cells13171441 (Aug 2024); https://doi.org/10.1016/j.jbc.2025.110002 (May 2025). Mandatory verification of identity - The gene symbol ATP6V0C (human; UniProt P27449) matches the proteolipid subunit c of the V‑ATPase Vo domain described in the cited sources, confirming organism and family/domain alignment. The mechanistic/structural descriptions of the c‑ring proteolipid are consistent with V‑ATPase proteolipid family membership and Vo localization (eaton2021theh+atpase(vatpase) pages 1-5, indrawinata2023structuralandfunctional pages 5-6, indrawinata2023structuralandfunctional pages 4-5). URL: https://doi.org/10.1152/ajpcell.00442.2020 (Mar 2021); https://doi.org/10.3389/fnmol.2023.1135015 (Jul 2023). Limitations and open questions - The retrieved excerpts do not provide direct, human cryo‑EM copy numbers for synaptic vesicles or inhibitor binding site maps specific to ATP6V0C; site‑specific pharmacology and 2024 synaptic vesicle structural quantitation therefore could not be cited here. Nonetheless, the cited 2023–2024 reviews and structural summaries establish the c‑ring mechanism, coupling stoichiometry, and disease links. Future integration of high‑resolution human cryo‑EM maps will further refine ATP6V0C’s stoichiometry across organelles and drug‑binding determinants (indrawinata2023structuralandfunctional pages 5-6, indrawinata2023structuralandfunctional pages 4-5, falace2024vatpasedysfunctionin pages 6-8, eaton2021theh+atpase(vatpase) pages 1-5). References 1. (eaton2021theh+atpase(vatpase) pages 1-5): Amity F. Eaton, Maria Merkulova, and Dennis Brown. The h+-atpase (v-atpase): from proton pump to signaling complex in health and disease. American Journal of Physiology-Cell Physiology, 320:C392-C414, Mar 2021. URL: https://doi.org/10.1152/ajpcell.00442.2020, doi:10.1152/ajpcell.00442.2020. This article has 164 citations. 2. (indrawinata2023structuralandfunctional pages 5-6): Karen Indrawinata, Peter Argiropoulos, and Shuzo Sugita. Structural and functional understanding of disease-associated mutations in v-atpase subunit a1 and other isoforms. Frontiers in Molecular Neuroscience, Jul 2023. URL: https://doi.org/10.3389/fnmol.2023.1135015, doi:10.3389/fnmol.2023.1135015. This article has 14 citations and is from a poor quality or predatory journal. 3. (indrawinata2023structuralandfunctional pages 4-5): Karen Indrawinata, Peter Argiropoulos, and Shuzo Sugita. Structural and functional understanding of disease-associated mutations in v-atpase subunit a1 and other isoforms. Frontiers in Molecular Neuroscience, Jul 2023. URL: https://doi.org/10.3389/fnmol.2023.1135015, doi:10.3389/fnmol.2023.1135015. This article has 14 citations and is from a poor quality or predatory journal. 4. (winkley2025abstract2474rogdi pages 17-21): Samuel Winkley and Patricia Kane. Abstract 2474 rogdi is the homolog of yeast rav2 and a novel rabconnectin-3 subunit. Journal of Biological Chemistry, 301:110002, May 2025. URL: https://doi.org/10.1016/j.jbc.2025.110002, doi:10.1016/j.jbc.2025.110002. This article has 0 citations and is from a domain leading peer-reviewed journal. 5. (falace2024vatpasedysfunctionin pages 6-8): Antonio Falace, Greta Volpedo, Marcello Scala, Federico Zara, Pasquale Striano, and Anna Fassio. V-atpase dysfunction in the brain: genetic insights and therapeutic opportunities. Cells, 13:1441, Aug 2024. URL: https://doi.org/10.3390/cells13171441, doi:10.3390/cells13171441. This article has 16 citations and is from a poor quality or predatory journal. ## Citations 1. indrawinata2023structuralandfunctional pages 5-6 2. falace2024vatpasedysfunctionin pages 6-8 3. indrawinata2023structuralandfunctional pages 4-5 4. https://doi.org/10.1152/ajpcell.00442.2020 5. https://doi.org/10.3389/fnmol.2023.1135015 6. https://doi.org/10.1016/j.jbc.2025.110002 7. https://doi.org/10.3390/cells13171441 8. https://doi.org/10.1152/ajpcell.00442.2020, 9. https://doi.org/10.3389/fnmol.2023.1135015, 10. https://doi.org/10.1016/j.jbc.2025.110002, 11. https://doi.org/10.3390/cells13171441,