id: P21281 gene_symbol: ATP6V1B2 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: 'ATP6V1B2 encodes the non-catalytic B subunit (brain isoform, B2) of the V1 peripheral domain of the vacuolar-type H+-ATPase (V-ATPase). The V1 complex hydrolyzes ATP to power proton translocation through the membrane-embedded V0 domain. Three non-catalytic B2 subunits alternate with three catalytic A subunits (ATP6V1A) to form the catalytic AB heterohexameric ring of V1. ATP6V1B2 is the ubiquitously expressed isoform of the B subunit, in contrast to the kidney-specific B1 isoform (ATP6V1B1). V-ATPase acidifies lysosomes, endosomes, Golgi, and secretory vesicles in all cell types; in specialized cells including renal intercalated cells and melanocytes, it is found at the apical plasma membrane and in melanosomes respectively. ATP6V1B2 can partially compensate for ATP6V1B1 in renal intercalated cells under baseline conditions but not under conditions of acid load. Dominant mutations in ATP6V1B2 cause two allelic syndromes: DDOD (dominant deafness-onychodystrophy syndrome, MIM:124480) and Zimmermann-Laband syndrome type 2 (ZLS2, MIM:616455).' existing_annotations: - term: id: GO:1902600 label: proton transmembrane transport evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Proton transmembrane transport is the primary biological process of V-ATPase. The B2 subunit is essential as the non-catalytic component of the catalytic AB hexamer. action: ACCEPT reason: This is the core biological process of V-ATPase; the B2 subunit is required for V1 complex assembly and thus for proton transport. supported_by: - reference_id: PMID:33065002 supporting_text: Vesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. reference_section_type: ABSTRACT - term: id: GO:0000221 label: vacuolar proton-transporting V-type ATPase, V1 domain evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of review: summary: ATP6V1B2 is definitionally a subunit of the V1 domain. This is a core structural annotation. action: ACCEPT reason: The B subunit is one of the defining subunits of the V1 domain, present in three copies alternating with three A subunits. supported_by: - reference_id: PMID:33065002 supporting_text: 'The V 1 ATPase is composed of three copies of subunits A, B, E, and G, and one copy of subunit C, D, F, and H' reference_section_type: INTRODUCTION - term: id: GO:0005886 label: plasma membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: V-ATPase can be active at the plasma membrane in specialized cells (osteoclasts, renal intercalated cells). The is_active_in qualifier is appropriate. action: KEEP_AS_NON_CORE reason: Plasma membrane localization is real but cell-type-specific; not the primary ubiquitous functional location for V-ATPase. supported_by: - reference_id: file:human/ATP6V1B2/ATP6V1B2-uniprot.txt supporting_text: Non-catalytic subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons reference_section_type: DATABASE_ENTRY - term: id: GO:0016324 label: apical plasma membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Apical plasma membrane V-ATPase is found in renal intercalated cells and other polarized epithelial cells. The IBA annotation infers from orthologs. action: KEEP_AS_NON_CORE reason: Apical plasma membrane is a real but cell-type-specific localization. Not the core ubiquitous function. - term: id: GO:0007035 label: vacuolar acidification evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Vacuolar acidification is the core biological process of V-ATPase. Well supported by the primary literature. action: ACCEPT reason: Vacuolar/lysosomal acidification is the primary biological function of V-ATPase, and the B2 subunit is required for V1 assembly and function. supported_by: - reference_id: PMID:32001091 supporting_text: V-ATPases are the primary source of organellar acidification in all eukaryotes, making them essential for many fundamental cellular processes reference_section_type: ABSTRACT - term: id: GO:0005524 label: ATP binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: The B subunit does not have the catalytic ATP-binding site (that is on the A subunit) but it does bind ATP/ADP non-catalytically. The B2 subunit is part of the ATP-binding interface. action: ACCEPT reason: The B subunit participates in ATP binding at the non-catalytic AB interface. IEA from InterPro is appropriate. - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: The V1 domain including B2 subunit can be cytoplasmic during regulated V1-V0 disassembly under nutrient starvation. action: KEEP_AS_NON_CORE reason: Cytoplasmic localization reflects reversible V1-V0 disassembly; a real but non-primary functional state. - term: id: GO:0016324 label: apical plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Apical plasma membrane localization from automated annotation; consistent with the IDA evidence from PMID:29993276. action: KEEP_AS_NON_CORE reason: Apical membrane localization is real but cell-type-specific (kidney tubule). - term: id: GO:0030665 label: clathrin-coated vesicle membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Clathrin-coated vesicle membrane localization from UniProt by similarity with rat B2. V-ATPase acidifies clathrin-coated vesicles during endocytosis. action: KEEP_AS_NON_CORE reason: Legitimate localization derived from ortholog data but not the primary functional compartment. - term: id: GO:0030672 label: synaptic vesicle membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Synaptic vesicle membrane localization from UniProt by similarity with rat B2. V-ATPase acidifies synaptic vesicles to enable neurotransmitter loading. action: KEEP_AS_NON_CORE reason: Synaptic vesicle localization is a specialized neuronal function; non-core relative to ubiquitous lysosomal function. - term: id: GO:0033180 label: proton-transporting V-type ATPase, V1 domain evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: part_of review: summary: Structural annotation - B2 is a component of the V1 domain. Consistent with all structural data. action: ACCEPT reason: Core structural annotation for the B subunit of V-ATPase V1 domain. - term: id: GO:0042470 label: melanosome evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Melanosome localization from UniProt derived from the proteomics study (PMID:12643545) showing V-ATPase B2 in melanosomes. action: KEEP_AS_NON_CORE reason: Melanosome localization is real and experimentally supported but is a cell-type-specific function in melanocytes, not the core ubiquitous localization. supported_by: - reference_id: PMID:12643545 supporting_text: melanocytes, which synthesize and deposit the pigment in specialized membrane-bound organelles known as melanosomes reference_section_type: ABSTRACT - term: id: GO:0046034 label: ATP metabolic process evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: ATP metabolic process is too broad. V-ATPase hydrolyzes ATP but this is coupled to proton transport. The more specific proton transport annotations capture the biology better. action: MARK_AS_OVER_ANNOTATED reason: Too broad; the specific proton transport and acidification terms are more informative for V-ATPase function. - term: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: The B2 subunit contributes to the proton-transporting ATPase activity as the non-catalytic component of the AB hexamer. The enables qualifier (vs contributes_to) should be noted. action: ACCEPT reason: Core molecular function of V-ATPase. The B subunit enables this function as part of the complex even though it lacks the catalytic residues itself. - term: id: GO:1902600 label: proton transmembrane transport evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: Duplicate annotation from different automated pipeline. Core function. action: ACCEPT reason: Proton transmembrane transport is the primary biological process of V-ATPase. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: Generic protein binding annotation from a large-scale proteome-wide interactome study. Not informative about specific function of ATP6V1B2. action: MARK_AS_OVER_ANNOTATED reason: Protein binding (GO:0005515) is uninformative. High-throughput interactome studies are not gene-specific and this term does not capture any relevant biology. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 qualifier: enables review: summary: Generic protein binding from a neurodegenerative disease proteins interactome study. Not informative about specific ATP6V1B2 function. action: MARK_AS_OVER_ANNOTATED reason: Generic protein binding. Large-scale interactome study does not provide gene-specific functional information. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:34159380 qualifier: enables review: summary: Generic protein binding from a SARS-CoV-2 Nsp2 interactome study. ATP6V1B2 was identified as interacting with viral Nsp2 but this represents a host-pathogen interaction, not a core cellular function. action: MARK_AS_OVER_ANNOTATED reason: Generic protein binding in a viral interactome context does not capture core cellular function of ATP6V1B2. - term: id: GO:0000221 label: vacuolar proton-transporting V-type ATPase, V1 domain evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: part_of review: summary: Duplicate V1 domain annotation from a different automated pipeline. action: ACCEPT reason: Core structural annotation. Consistent with all evidence. - term: id: GO:0001726 label: ruffle evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Ruffle localization from Ensembl Compara ortholog transfer. Ruffles are actin-rich plasma membrane protrusions; V-ATPase at ruffles has been described in osteoclasts and migrating cells. action: KEEP_AS_NON_CORE reason: Ruffle localization is a specialized cell-context annotation (osteoclasts, migrating cells), not a core ubiquitous localization. - term: id: GO:0005829 label: cytosol evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Cytosolic localization from Ensembl Compara ortholog transfer; reflects free V1 domain during regulated disassembly. action: KEEP_AS_NON_CORE reason: Cytosol annotation reflects real V1 disassembly state but is non-primary functional localization. - term: id: GO:0005886 label: plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Plasma membrane localization from ortholog transfer. Real but cell-type-specific. action: KEEP_AS_NON_CORE reason: Cell-type-specific localization; not the primary ubiquitous functional localization. - term: id: GO:0005902 label: microvillus evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Microvillus localization from ortholog transfer. V-ATPase is present in apical microvilli of polarized epithelial cells. action: KEEP_AS_NON_CORE reason: Specialized apical structure in polarized epithelial cells; non-core for ubiquitous function. - term: id: GO:0097401 label: synaptic vesicle lumen acidification evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: V-ATPase acidifies synaptic vesicles to drive neurotransmitter loading in neurons. This is a specialized neuronal function. action: KEEP_AS_NON_CORE reason: Synaptic vesicle lumen acidification is a specialized neuronal function; real but not the core ubiquitous process for V-ATPase B2. - term: id: GO:0098850 label: extrinsic component of synaptic vesicle membrane evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: is_active_in review: summary: V1 domain is an extrinsic component of the synaptic vesicle membrane; it can dissociate from V0. The annotation reflects the neuronal context. action: KEEP_AS_NON_CORE reason: Specialized neuronal localization; non-core for the ubiquitous function. - term: id: GO:0005737 label: cytoplasm evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Cytoplasm annotation by sequence similarity; consistent with regulated V1-V0 disassembly. action: KEEP_AS_NON_CORE reason: Non-primary functional state; cytoplasm reflects free V1 complex. - term: id: GO:0042470 label: melanosome evidence_type: EXP original_reference_id: PMID:12643545 qualifier: located_in review: summary: Experimental detection of ATP6V1B2 in melanosomes by mass spectrometry from melanoma cell melanosomes. V-ATPase acidification is required for melanogenesis. action: KEEP_AS_NON_CORE reason: Melanosome localization is experimentally supported but is a specialized melanocyte-specific role; not the core ubiquitous localization of V-ATPase B2. supported_by: - reference_id: PMID:12643545 supporting_text: melanocytes, which synthesize and deposit the pigment in specialized membrane-bound organelles known as melanosomes reference_section_type: ABSTRACT - term: id: GO:0000221 label: vacuolar proton-transporting V-type ATPase, V1 domain evidence_type: IDA original_reference_id: PMID:33065002 qualifier: part_of review: summary: Cryo-EM structure directly confirms ATP6V1B2 as part of the V1 domain of the human V-ATPase complex. action: ACCEPT reason: Direct structural evidence from the complete human V-ATPase cryo-EM structure. supported_by: - reference_id: PMID:33065002 supporting_text: 'The V 1 ATPase is composed of three copies of subunits A, B, E, and G, and one copy of subunit C, D, F, and H' reference_section_type: INTRODUCTION - term: id: GO:0016324 label: apical plasma membrane evidence_type: IDA original_reference_id: PMID:29993276 qualifier: located_in review: summary: PMID:29993276 primarily documents B1 (ATP6V1B1) localization in apical membrane of kidney distal nephron. The paper also notes B2 expression in these segments but the primary IDA evidence is for B1. The annotation for B2 may be based on weak co-expression data. action: KEEP_AS_NON_CORE reason: While B2 is expressed in the kidney early distal nephron, this is a specialized renal function and not the primary ubiquitous function of V-ATPase B2. The evidence from PMID:29993276 mainly pertains to B1. supported_by: - reference_id: PMID:29993276 supporting_text: the highly homologous B2 subunit, which has also been found expressed in the TAL, DCT, and CNT in addition to the ICs of rat and mouse kidney in early dis reference_section_type: INTRODUCTION - term: id: GO:0016241 label: regulation of macroautophagy evidence_type: NAS original_reference_id: PMID:22982048 qualifier: involved_in review: summary: V-ATPase acidification of lysosomes is required for autophagic flux. However, the reference paper studies lipofuscin formation in senescent cells and uses V-ATPase inhibitors as experimental tools, not directly studying ATP6V1B2. action: KEEP_AS_NON_CORE reason: V-ATPase is required for lysosomal function which enables autophagy, but this is an indirect downstream consequence of the core proton pump function. The NAS annotation from a non-V-ATPase-specific paper should be kept but marked as non-core. supported_by: - reference_id: PMID:22982048 supporting_text: Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts. reference_section_type: TITLE - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:23533145 qualifier: located_in review: summary: V-ATPase B2 detected in exosome proteomics. Likely reflects contamination or non-specific co-purification from lysosomes/endosomes during exosome isolation. action: MARK_AS_OVER_ANNOTATED reason: Exosome proteomics HDA annotation for V-ATPase subunits likely represents contamination. V-ATPase B2 is a lysosomal/endosomal enzyme and its presence in exosome fractions is not a primary functional localization. - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19199708 qualifier: located_in review: summary: V-ATPase B2 detected in parotid gland exosome proteomics. Likely contamination. action: MARK_AS_OVER_ANNOTATED reason: High-throughput proteomics exosome annotation; not a primary functional localization for V-ATPase. - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19056867 qualifier: located_in review: summary: V-ATPase B2 detected in urinary exosome proteomics. Likely contamination. action: MARK_AS_OVER_ANNOTATED reason: High-throughput proteomics exosome annotation; not a primary functional localization for V-ATPase. - term: id: GO:0005765 label: lysosomal membrane evidence_type: HDA original_reference_id: PMID:17897319 qualifier: located_in review: summary: Proteomics study of lysosomal membranes detects V-ATPase B2. Supports lysosomal membrane localization. action: ACCEPT reason: Large-scale proteomics of lysosomal membranes directly confirms V-ATPase B2 at the lysosomal membrane, which is its primary functional localization. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-1222516 qualifier: located_in review: summary: Reactome TAS annotation for cytosolic V-ATPase. Reflects V1 domain dissociation. action: KEEP_AS_NON_CORE reason: Non-primary functional state; V1 can be cytosolic during regulated disassembly. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5252133 qualifier: located_in review: summary: Reactome TAS annotation for cytosol. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-74723 qualifier: located_in review: summary: Reactome TAS annotation for cytosol. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-917841 qualifier: located_in review: summary: Reactome TAS annotation for cytosol. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9639286 qualifier: located_in review: summary: Reactome TAS annotation for cytosol in mTOR/Rag GTPase pathway context. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9640167 qualifier: located_in review: summary: Reactome TAS annotation for cytosol. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9640168 qualifier: located_in review: summary: Reactome TAS annotation for cytosol. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9640175 qualifier: located_in review: summary: Reactome TAS annotation for cytosol. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9640195 qualifier: located_in review: summary: Reactome TAS annotation for cytosol. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9645598 qualifier: located_in review: summary: Reactome TAS annotation for cytosol. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9645608 qualifier: located_in review: summary: Reactome TAS annotation for cytosol in mTORC1 recruitment context. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9646468 qualifier: located_in review: summary: Reactome TAS annotation for cytosol. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9858918 qualifier: located_in review: summary: Reactome TAS annotation for cytosol in MITF-M-dependent ATP6V1B2 gene expression context. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - term: id: GO:0005829 label: cytosol evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Ortholog-based cytosol annotation. action: KEEP_AS_NON_CORE reason: Non-primary functional state. - term: id: GO:0005886 label: plasma membrane evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Ortholog-based plasma membrane annotation. Cell-type-specific localization. action: KEEP_AS_NON_CORE reason: Cell-type-specific localization; not the primary ubiquitous function. - term: id: GO:0015078 label: proton transmembrane transporter activity evidence_type: TAS original_reference_id: PMID:2145275 qualifier: enables review: summary: The original 1990 paper identifies the B subunit as part of the catalytic complex of V-ATPase. The proton transmembrane transporter activity annotation is correct for the complex. action: ACCEPT reason: This TAS annotation from the original characterization paper is correct; the V1 complex including B2 is required for proton transporter activity. supported_by: - reference_id: PMID:2145275 supporting_text: The B subunit (approximately 60 kDa) of the vacuolar H(+)-ATPase is one of the two major subunits comprising the hydrophilic catalytic complex of the enzyme. reference_section_type: ABSTRACT - term: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism evidence_type: TAS original_reference_id: PMID:2145275 qualifier: enables review: summary: The 1990 paper establishes B2 as a component of the vacuolar H+-ATPase; proton-transporting ATPase by rotational mechanism is the core molecular function. action: ACCEPT reason: Core molecular function annotation from the original characterization paper. supported_by: - reference_id: PMID:2145275 supporting_text: The B subunit (approximately 60 kDa) of the vacuolar H(+)-ATPase is one of the two major subunits comprising the hydrophilic catalytic complex of the enzyme. reference_section_type: ABSTRACT - term: id: GO:1902600 label: proton transmembrane transport evidence_type: TAS original_reference_id: PMID:2145275 qualifier: involved_in review: summary: Proton transmembrane transport from the original characterization paper. Core function. action: ACCEPT reason: Core biological process annotation for V-ATPase B2. supported_by: - reference_id: PMID:2145275 supporting_text: The B subunit (approximately 60 kDa) of the vacuolar H(+)-ATPase is one of the two major subunits comprising the hydrophilic catalytic complex of the enzyme. reference_section_type: ABSTRACT core_functions: - description: ATP6V1B2 is the non-catalytic B subunit of the V1 domain of V-ATPase. Three B2 subunits alternate with three catalytic A subunits to form the AB heterohexameric ring of V1. B2 is required for V1 complex assembly and enables proton translocation by the holoenzyme. contributes_to_molecular_function: id: GO:0046961 label: proton-transporting ATPase activity, rotational mechanism molecular_function: id: GO:0015078 label: proton transmembrane transporter activity directly_involved_in: - id: GO:1902600 label: proton transmembrane transport - id: GO:0007035 label: vacuolar acidification locations: - id: GO:0005765 label: lysosomal membrane in_complex: id: GO:0000221 label: vacuolar proton-transporting V-type ATPase, V1 domain suggested_questions: - question: What is the molecular basis by which dominant mutations in ATP6V1B2 cause DDOD versus ZLS2 — are these gain-of-function, dominant-negative, or haploinsufficiency effects? - question: How does ATP6V1B2 (B2) compensate for ATP6V1B1 (B1) in renal intercalated cells, and why is this compensation insufficient under acid load? - question: Does the interaction between ATP6V1B2 and huntingtin (HTT) have functional consequences for V-ATPase function or lysosomal biology in neurons? - question: What is the relative contribution of ATP6V1B2 versus ATP6V1B1 to V-ATPase function in different cell types, and are there cell types where only B2 is expressed? suggested_experiments: - description: Structural analysis by cryo-EM of V-ATPase containing DDOD/ZLS2 mutant B2 subunits to determine the structural basis of dominant disease mutations. hypothesis: Dominant mutations in ATP6V1B2 alter V1 complex assembly or rotation dynamics in a gain-of-function or dominant-negative manner. - description: Knock-in of the Arg485Pro ZLS2 mutation in mouse to establish the disease mechanism and test whether the phenotype can be rescued by gene therapy approaches. hypothesis: The Arg485Pro mutation causes ZLS2 through a dominant mechanism that can be distinguished from the DDOD-causing mutations. - description: Comparative lysosomal pH measurements in primary cells from DDOD and ZLS2 patients to determine if the two diseases have different lysosomal acidification phenotypes. hypothesis: Different dominant ATP6V1B2 mutations cause distinct lysosomal pH alterations that correspond to the different clinical presentations. - description: Single-cell RNA-seq in human kidney to determine the precise cell-type distribution of ATP6V1B2 vs ATP6V1B1 expression. hypothesis: ATP6V1B2 is more broadly expressed than ATP6V1B1 throughout the nephron, explaining why B2 can partially compensate for B1 loss only at baseline conditions. references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:2145275 title: An mRNA from human brain encodes an isoform of the B subunit of the vacuolar H(+)-ATPase. findings: - statement: First identification of the brain B subunit isoform (B2) of V-ATPase; established that brain and kidney B subunit cDNAs represent different isoforms. - statement: The B subunit is one of the two major subunits of the hydrophilic catalytic complex of V-ATPase. - id: PMID:12643545 title: 'Proteomic analysis of early melanosomes: identification of novel melanosomal proteins.' findings: - statement: Mass spectrometry detection of V-ATPase B2 (ATP6V1B2) in stage I-IV melanosomes from melanoma cells. - id: PMID:17897319 title: Integral and associated lysosomal membrane proteins. findings: - statement: Large-scale proteomics of lysosomal membrane fraction confirms V-ATPase B2 presence at lysosomal membrane. - id: PMID:19056867 title: Large-scale proteomics and phosphoproteomics of urinary exosomes. findings: - statement: Mass spectrometry detection of ATP6V1B2 in urinary exosome fraction; likely a contaminant. - id: PMID:19199708 title: Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). findings: - statement: Mass spectrometry detection of ATP6V1B2 in parotid gland exosomes; likely a contaminant. - id: PMID:22982048 title: Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts. findings: - statement: Used V-ATPase inhibitors to block lysosomal activity; demonstrates V-ATPase dependence of macroautophagy, but not a primary study of ATP6V1B2 function. - id: PMID:23533145 title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. findings: - statement: Mass spectrometry detection of ATP6V1B2 in urinary exosomes; likely a contaminant. - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: - statement: High-throughput yeast two-hybrid screen identifies ATP6V1B2 protein interactions; data used for IPI protein binding annotation. - id: PMID:29993276 title: H(+)-ATPase B1 subunit localizes to thick ascending limb and distal convoluted tubule of rodent and human kidney. findings: - statement: B1 subunit localizes to apical membrane domains of thick ascending limb and distal convoluted tubule in human kidney. - statement: B2 subunit is also expressed in TAL, DCT, and CNT in addition to intercalated cells; it colocalizes with B1 in early distal nephron. - id: PMID:32001091 title: Structure and Roles of V-type ATPases. findings: - statement: Comprehensive review of V-ATPase structure, function, and disease associations. - statement: V-ATPase is the primary organellar acidification system in eukaryotes. - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: - statement: ATP6V1B2 identified in neurodegenerative disease protein interactome; interacts with HTT, NEFL, and other neurodegeneration-associated proteins. - id: PMID:33065002 title: Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly. findings: - statement: Complete human V-ATPase cryo-EM structure confirms three copies of B subunit (including B2) in the V1 hexameric ring. - statement: ATP6V1B2 is the non-catalytic B subunit of V1 domain. - id: PMID:34159380 title: Nsp2 has the potential to be a drug target revealed by global identification of SARS-CoV-2 Nsp2-interacting proteins. findings: - statement: ATP6V1B2 identified as a SARS-CoV-2 Nsp2-interacting protein; represents a host-pathogen interaction. - id: Reactome:R-HSA-1222516 title: Intraphagosomal pH is lowered to 5 by V-ATPase findings: [] - id: Reactome:R-HSA-5252133 title: ATP6AP1 binds V-ATPase findings: [] - id: Reactome:R-HSA-74723 title: Endosome acidification findings: [] - id: Reactome:R-HSA-917841 title: Acidification of Tf:TfR1 containing endosome findings: [] - id: Reactome:R-HSA-9639286 title: RRAGC,D exchanges GTP for GDP findings: [] - id: Reactome:R-HSA-9640167 title: RRAGA,B exchanges GDP for GTP findings: [] - id: Reactome:R-HSA-9640168 title: v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP:SLC38A9:Arginine dissociates yielding v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP and SLC38A9:Arginine findings: [] - id: Reactome:R-HSA-9640175 title: v-ATPase:Ragulator:RagA,B:GDP:RagC,D:GDP binds SLC38A9:Arginine findings: [] - id: Reactome:R-HSA-9640195 title: RRAGA,B hydrolyzes GTP findings: [] - id: Reactome:R-HSA-9645598 title: RRAGC,D hydrolyzes GTP findings: [] - id: Reactome:R-HSA-9645608 title: v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP binds mTORC1 findings: [] - id: Reactome:R-HSA-9646468 title: mTORC1 binds RHEB:GTP findings: [] - id: Reactome:R-HSA-9858918 title: MITF-M-dependent ATP6V1B2 gene expression findings: []