ATP6V1B2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:1902600 proton transmembrane transport	IBA GO_REF:0000033	ACCEPT	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. Reason: This is the core biological process of V-ATPase; the B2 subunit is required for V1 complex assembly and thus for proton transport. Supporting Evidence: PMID:33065002 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.
GO:0000221 vacuolar proton-transporting V-type ATPase, V1 domain	IBA GO_REF:0000033	ACCEPT	Summary: ATP6V1B2 is definitionally a subunit of the V1 domain. This is a core structural annotation. Reason: The B subunit is one of the defining subunits of the V1 domain, present in three copies alternating with three A subunits. Supporting Evidence: PMID:33065002 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
GO:0005886 plasma membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: V-ATPase can be active at the plasma membrane in specialized cells (osteoclasts, renal intercalated cells). The is_active_in qualifier is appropriate. Reason: Plasma membrane localization is real but cell-type-specific; not the primary ubiquitous functional location for V-ATPase. Supporting Evidence: file:human/ATP6V1B2/ATP6V1B2-uniprot.txt 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
GO:0016324 apical plasma membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Apical plasma membrane V-ATPase is found in renal intercalated cells and other polarized epithelial cells. The IBA annotation infers from orthologs. Reason: Apical plasma membrane is a real but cell-type-specific localization. Not the core ubiquitous function.
GO:0007035 vacuolar acidification	IBA GO_REF:0000033	ACCEPT	Summary: Vacuolar acidification is the core biological process of V-ATPase. Well supported by the primary literature. Reason: Vacuolar/lysosomal acidification is the primary biological function of V-ATPase, and the B2 subunit is required for V1 assembly and function. Supporting Evidence: PMID:32001091 V-ATPases are the primary source of organellar acidification in all eukaryotes, making them essential for many fundamental cellular processes
GO:0005524 ATP binding	IEA GO_REF:0000002	ACCEPT	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. Reason: The B subunit participates in ATP binding at the non-catalytic AB interface. IEA from InterPro is appropriate.
GO:0005737 cytoplasm	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: The V1 domain including B2 subunit can be cytoplasmic during regulated V1-V0 disassembly under nutrient starvation. Reason: Cytoplasmic localization reflects reversible V1-V0 disassembly; a real but non-primary functional state.
GO:0016324 apical plasma membrane	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Apical plasma membrane localization from automated annotation; consistent with the IDA evidence from PMID:29993276. Reason: Apical membrane localization is real but cell-type-specific (kidney tubule).
GO:0030665 clathrin-coated vesicle membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Clathrin-coated vesicle membrane localization from UniProt by similarity with rat B2. V-ATPase acidifies clathrin-coated vesicles during endocytosis. Reason: Legitimate localization derived from ortholog data but not the primary functional compartment.
GO:0030672 synaptic vesicle membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Synaptic vesicle membrane localization from UniProt by similarity with rat B2. V-ATPase acidifies synaptic vesicles to enable neurotransmitter loading. Reason: Synaptic vesicle localization is a specialized neuronal function; non-core relative to ubiquitous lysosomal function.
GO:0033180 proton-transporting V-type ATPase, V1 domain	IEA GO_REF:0000002	ACCEPT	Summary: Structural annotation - B2 is a component of the V1 domain. Consistent with all structural data. Reason: Core structural annotation for the B subunit of V-ATPase V1 domain.
GO:0042470 melanosome	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Melanosome localization from UniProt derived from the proteomics study (PMID:12643545) showing V-ATPase B2 in melanosomes. Reason: Melanosome localization is real and experimentally supported but is a cell-type-specific function in melanocytes, not the core ubiquitous localization. Supporting Evidence: PMID:12643545 melanocytes, which synthesize and deposit the pigment in specialized membrane-bound organelles known as melanosomes
GO:0046034 ATP metabolic process	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	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. Reason: Too broad; the specific proton transport and acidification terms are more informative for V-ATPase function.
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IEA GO_REF:0000002	ACCEPT	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. 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.
GO:1902600 proton transmembrane transport	IEA GO_REF:0000120	ACCEPT	Summary: Duplicate annotation from different automated pipeline. Core function. Reason: Proton transmembrane transport is the primary biological process of V-ATPase.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation from a large-scale proteome-wide interactome study. Not informative about specific function of ATP6V1B2. Reason: Protein binding (GO:0005515) is uninformative. High-throughput interactome studies are not gene-specific and this term does not capture any relevant biology.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a neurodegenerative disease proteins interactome study. Not informative about specific ATP6V1B2 function. Reason: Generic protein binding. Large-scale interactome study does not provide gene-specific functional information.
GO:0005515 protein binding	IPI PMID:34159380 Nsp2 has the potential to be a drug target revealed by globa...	MARK AS OVER ANNOTATED	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. Reason: Generic protein binding in a viral interactome context does not capture core cellular function of ATP6V1B2.
GO:0000221 vacuolar proton-transporting V-type ATPase, V1 domain	IEA GO_REF:0000120	ACCEPT	Summary: Duplicate V1 domain annotation from a different automated pipeline. Reason: Core structural annotation. Consistent with all evidence.
GO:0001726 ruffle	IEA GO_REF:0000107	KEEP AS NON CORE	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. Reason: Ruffle localization is a specialized cell-context annotation (osteoclasts, migrating cells), not a core ubiquitous localization.
GO:0005829 cytosol	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Cytosolic localization from Ensembl Compara ortholog transfer; reflects free V1 domain during regulated disassembly. Reason: Cytosol annotation reflects real V1 disassembly state but is non-primary functional localization.
GO:0005886 plasma membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Plasma membrane localization from ortholog transfer. Real but cell-type-specific. Reason: Cell-type-specific localization; not the primary ubiquitous functional localization.
GO:0005902 microvillus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Microvillus localization from ortholog transfer. V-ATPase is present in apical microvilli of polarized epithelial cells. Reason: Specialized apical structure in polarized epithelial cells; non-core for ubiquitous function.
GO:0097401 synaptic vesicle lumen acidification	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: V-ATPase acidifies synaptic vesicles to drive neurotransmitter loading in neurons. This is a specialized neuronal function. Reason: Synaptic vesicle lumen acidification is a specialized neuronal function; real but not the core ubiquitous process for V-ATPase B2.
GO:0098850 extrinsic component of synaptic vesicle membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: V1 domain is an extrinsic component of the synaptic vesicle membrane; it can dissociate from V0. The annotation reflects the neuronal context. Reason: Specialized neuronal localization; non-core for the ubiquitous function.
GO:0005737 cytoplasm	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Cytoplasm annotation by sequence similarity; consistent with regulated V1-V0 disassembly. Reason: Non-primary functional state; cytoplasm reflects free V1 complex.
GO:0042470 melanosome	EXP PMID:12643545 Proteomic analysis of early melanosomes: identification of n...	KEEP AS NON CORE	Summary: Experimental detection of ATP6V1B2 in melanosomes by mass spectrometry from melanoma cell melanosomes. V-ATPase acidification is required for melanogenesis. Reason: Melanosome localization is experimentally supported but is a specialized melanocyte-specific role; not the core ubiquitous localization of V-ATPase B2. Supporting Evidence: PMID:12643545 melanocytes, which synthesize and deposit the pigment in specialized membrane-bound organelles known as melanosomes
GO:0000221 vacuolar proton-transporting V-type ATPase, V1 domain	IDA PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: Cryo-EM structure directly confirms ATP6V1B2 as part of the V1 domain of the human V-ATPase complex. Reason: Direct structural evidence from the complete human V-ATPase cryo-EM structure. Supporting Evidence: PMID:33065002 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
GO:0016324 apical plasma membrane	IDA PMID:29993276 H(+)-ATPase B1 subunit localizes to thick ascending limb and...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:29993276 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
GO:0016241 regulation of macroautophagy	NAS PMID:22982048 Lipofuscin is formed independently of macroautophagy and lys...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:22982048 Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts.
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	MARK AS OVER ANNOTATED	Summary: V-ATPase B2 detected in exosome proteomics. Likely reflects contamination or non-specific co-purification from lysosomes/endosomes during exosome isolation. 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.
GO:0070062 extracellular exosome	HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid...	MARK AS OVER ANNOTATED	Summary: V-ATPase B2 detected in parotid gland exosome proteomics. Likely contamination. Reason: High-throughput proteomics exosome annotation; not a primary functional localization for V-ATPase.
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	MARK AS OVER ANNOTATED	Summary: V-ATPase B2 detected in urinary exosome proteomics. Likely contamination. Reason: High-throughput proteomics exosome annotation; not a primary functional localization for V-ATPase.
GO:0005765 lysosomal membrane	HDA PMID:17897319 Integral and associated lysosomal membrane proteins.	ACCEPT	Summary: Proteomics study of lysosomal membranes detects V-ATPase B2. Supports lysosomal membrane localization. Reason: Large-scale proteomics of lysosomal membranes directly confirms V-ATPase B2 at the lysosomal membrane, which is its primary functional localization.
GO:0005829 cytosol	TAS Reactome:R-HSA-1222516	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosolic V-ATPase. Reflects V1 domain dissociation. Reason: Non-primary functional state; V1 can be cytosolic during regulated disassembly.
GO:0005829 cytosol	TAS Reactome:R-HSA-5252133	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Non-primary functional state.
GO:0005829 cytosol	TAS Reactome:R-HSA-74723	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Non-primary functional state.
GO:0005829 cytosol	TAS Reactome:R-HSA-917841	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Non-primary functional state.
GO:0005829 cytosol	TAS Reactome:R-HSA-9639286	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol in mTOR/Rag GTPase pathway context. Reason: Non-primary functional state.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640167	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Non-primary functional state.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640168	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Non-primary functional state.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640175	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Non-primary functional state.
GO:0005829 cytosol	TAS Reactome:R-HSA-9640195	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Non-primary functional state.
GO:0005829 cytosol	TAS Reactome:R-HSA-9645598	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Non-primary functional state.
GO:0005829 cytosol	TAS Reactome:R-HSA-9645608	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol in mTORC1 recruitment context. Reason: Non-primary functional state.
GO:0005829 cytosol	TAS Reactome:R-HSA-9646468	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol. Reason: Non-primary functional state.
GO:0005829 cytosol	TAS Reactome:R-HSA-9858918	KEEP AS NON CORE	Summary: Reactome TAS annotation for cytosol in MITF-M-dependent ATP6V1B2 gene expression context. Reason: Non-primary functional state.
GO:0005829 cytosol	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Ortholog-based cytosol annotation. Reason: Non-primary functional state.
GO:0005886 plasma membrane	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Ortholog-based plasma membrane annotation. Cell-type-specific localization. Reason: Cell-type-specific localization; not the primary ubiquitous function.
GO:0015078 proton transmembrane transporter activity	TAS PMID:2145275 An mRNA from human brain encodes an isoform of the B subunit...	ACCEPT	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. Reason: This TAS annotation from the original characterization paper is correct; the V1 complex including B2 is required for proton transporter activity. Supporting Evidence: PMID:2145275 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.
GO:0046961 proton-transporting ATPase activity, rotational mechanism	TAS PMID:2145275 An mRNA from human brain encodes an isoform of the B subunit...	ACCEPT	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. Reason: Core molecular function annotation from the original characterization paper. Supporting Evidence: PMID:2145275 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.
GO:1902600 proton transmembrane transport	TAS PMID:2145275 An mRNA from human brain encodes an isoform of the B subunit...	ACCEPT	Summary: Proton transmembrane transport from the original characterization paper. Core function. Reason: Core biological process annotation for V-ATPase B2. Supporting Evidence: PMID:2145275 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.

Gene Description

Existing Annotations Review

Core Functions

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.

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