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.

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.

Molecular Function:

proton transmembrane transporter activity

Directly Involved In:

proton transmembrane transport vacuolar acidification

Cellular Locations:

lysosomal membrane

In Complex:

vacuolar proton-transporting V-type ATPase, V1 domain

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:2145275

An mRNA from human brain encodes an isoform of the B subunit of the vacuolar H(+)-ATPase.

First identification of the brain B subunit isoform (B2) of V-ATPase; established that brain and kidney B subunit cDNAs represent different isoforms.
The B subunit is one of the two major subunits of the hydrophilic catalytic complex of V-ATPase.

PMID:12643545

Proteomic analysis of early melanosomes: identification of novel melanosomal proteins.

Mass spectrometry detection of V-ATPase B2 (ATP6V1B2) in stage I-IV melanosomes from melanoma cells.

PMID:17897319

Integral and associated lysosomal membrane proteins.

Large-scale proteomics of lysosomal membrane fraction confirms V-ATPase B2 presence at lysosomal membrane.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

Mass spectrometry detection of ATP6V1B2 in urinary exosome fraction; likely a contaminant.

PMID:19199708

Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).

Mass spectrometry detection of ATP6V1B2 in parotid gland exosomes; likely a contaminant.

PMID:22982048

Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts.

Used V-ATPase inhibitors to block lysosomal activity; demonstrates V-ATPase dependence of macroautophagy, but not a primary study of ATP6V1B2 function.

PMID:23533145

In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.

Mass spectrometry detection of ATP6V1B2 in urinary exosomes; likely a contaminant.

PMID:25416956

A proteome-scale map of the human interactome network.

High-throughput yeast two-hybrid screen identifies ATP6V1B2 protein interactions; data used for IPI protein binding annotation.

PMID:29993276

H(+)-ATPase B1 subunit localizes to thick ascending limb and distal convoluted tubule of rodent and human kidney.

B1 subunit localizes to apical membrane domains of thick ascending limb and distal convoluted tubule in human kidney.
B2 subunit is also expressed in TAL, DCT, and CNT in addition to intercalated cells; it colocalizes with B1 in early distal nephron.

PMID:32001091

Structure and Roles of V-type ATPases.

Comprehensive review of V-ATPase structure, function, and disease associations.
V-ATPase is the primary organellar acidification system in eukaryotes.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

ATP6V1B2 identified in neurodegenerative disease protein interactome; interacts with HTT, NEFL, and other neurodegeneration-associated proteins.

PMID:33065002

Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly.

Complete human V-ATPase cryo-EM structure confirms three copies of B subunit (including B2) in the V1 hexameric ring.
ATP6V1B2 is the non-catalytic B subunit of V1 domain.

PMID:34159380

Nsp2 has the potential to be a drug target revealed by global identification of SARS-CoV-2 Nsp2-interacting proteins.

ATP6V1B2 identified as a SARS-CoV-2 Nsp2-interacting protein; represents a host-pathogen interaction.

Reactome:R-HSA-1222516

Intraphagosomal pH is lowered to 5 by V-ATPase

Reactome:R-HSA-5252133

ATP6AP1 binds V-ATPase

Reactome:R-HSA-74723

Endosome acidification

Reactome:R-HSA-917841

Acidification of Tf:TfR1 containing endosome

Reactome:R-HSA-9639286

RRAGC,D exchanges GTP for GDP

Reactome:R-HSA-9640167

RRAGA,B exchanges GDP for GTP

Reactome:R-HSA-9640168

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

Reactome:R-HSA-9640175

v-ATPase:Ragulator:RagA,B:GDP:RagC,D:GDP binds SLC38A9:Arginine

Reactome:R-HSA-9640195

RRAGA,B hydrolyzes GTP

Reactome:R-HSA-9645598

RRAGC,D hydrolyzes GTP

Reactome:R-HSA-9645608

v-ATPase:Ragulator:RRAGA,B:GTP:RRAGC,D:GDP binds mTORC1

Reactome:R-HSA-9646468

mTORC1 binds RHEB:GTP

Reactome:R-HSA-9858918

MITF-M-dependent ATP6V1B2 gene expression

Suggested Experiments

Experiment: 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.

Experiment: 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.

Experiment: 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.

Experiment: 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.

Deep Research

Falcon

(ATP6V1B2-deep-research-falcon.md)

Comprehensive Research Report: ATP6V1B2 (UniProt P21281) - V-type Proton ATPase Subunit B, Brain Isoform Falcon

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.

Comprehensive Research Report: ATP6V1B2 (UniProt P21281) - V-type Proton ATPase Subunit B, Brain Isoform

Gene and Protein Identity

ATP6V1B2 encodes the V-type proton ATPase subunit B2 (V1B2), the brain-enriched isoform of the B subunit within the cytosolic V1 domain of the vacuolar H+-ATPase (V-ATPase) complex (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3). This protein belongs to the ATPase alpha/beta chains family and contains characteristic ATP-synthase domains (ATP-synt_ab, ATP-synt_ab_N, ATP-synt_VA_C), consistent with its role in ATP-driven proton pumping (eaton2021theh+atpase(vatpase) pages 1-5, wang2020structuresofa pages 1-3). In mammalian brain, ATP6V1B2 is a component of V-ATPase complexes enriched in synaptic vesicles and neuronal compartments, coassembling with V1 subunits A, C1, D, E1, F, G2, and H, as well as V0 subunits including a1, c, d1, ATP6AP1, and ATP6AP2 (abbas2020structureofvatpase pages 1-2, abbas2020structureofvatpase pages 2-4).

Primary Molecular Function and Catalytic Mechanism

ATP6V1B2 functions as a critical catalytic subunit within the V-ATPase, a multisubunit rotary proton pump responsible for acidification of intracellular organelles (eaton2021theh+atpase(vatpase) pages 1-5, abbas2020structureofvatpase pages 1-2). The V-ATPase complex comprises two main domains: the cytoplasmic V1 domain, which hydrolyzes ATP, and the membrane-embedded V0 domain, which translocates protons across membranes (eaton2021theh+atpase(vatpase) pages 1-5, eaton2021theh+atpase(vatpase) pages 5-9).

Catalytic Reaction and Mechanism

The overall catalytic reaction catalyzed by the V-ATPase complex is:

ATP + H2O → ADP + Pi + H+ (transported)

High-resolution cryo-electron microscopy structures of mammalian brain V-ATPase have defined the ATP:proton stoichiometry as approximately 3:10, meaning three ATP molecules are hydrolyzed to pump ten protons (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3). ATP6V1B2 itself does not directly translocate protons; rather, it contributes to the A3B3 hexameric head of the V1 domain where ATP hydrolysis occurs (wang2020structuresofa pages 1-3, abbas2020structureofvatpase pages 2-4, wang2020structuresofa pages 3-5). The B subunits alternate with A subunits around a pseudo-6-fold symmetry axis, forming the catalytic head that undergoes conformational changes during the catalytic cycle (wang2020structuresofa pages 3-5).

The mechanism involves ATP binding and hydrolysis in the V1 A3B3 head, which drives rotation of a central stalk composed of subunits D and F (wang2020structuresofa pages 3-5). This rotational energy is transmitted to the membrane-embedded V0 proton pore, causing cycles of protonation and deprotonation of lipid-exposed glutamic acid residues in the c-ring, thereby coupling ATP hydrolysis to directional proton transport (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3, abbas2020structureofvatpase pages 2-4).

Substrate Specificity

The primary substrate for V-ATPase is ATP, with the enzyme displaying high specificity for adenine nucleotides (eaton2021theh+atpase(vatpase) pages 1-5). The products are ADP, inorganic phosphate (Pi), and a proton gradient across the organelle membrane (eaton2021theh+atpase(vatpase) pages 1-5, eaton2021theh+atpase(vatpase) pages 5-9). The V-ATPase does not transport specific molecular cargo; instead, it establishes an electrochemical proton gradient (typically pH 4.5-5.0 in lysosomes) that energizes secondary transport processes and activates pH-dependent enzymes (eaton2021theh+atpase(vatpase) pages 1-5, eaton2021theh+atpase(vatpase) pages 5-9).

Structural Features and Domain Organization

Cryo-EM structural studies at near-atomic resolution (2.9-4.0 Å) have elucidated the architecture of human and rat brain V-ATPases containing ATP6V1B2 (abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5). ATP6V1B2 resides in the A3B3 hexameric head of the V1 complex, with three B2 subunits alternating with three A subunits (wang2020structuresofa pages 3-5). The B subunits exhibit three distinct conformational states during the catalytic cycle—closed, semi-open, and open—corresponding to different stages of ATP binding and hydrolysis (wang2020structuresofa pages 3-5).

Recent biochemical mapping has identified functional regions within ATP6V1B2, including an N-terminal region (residues 1-49) that is essential for interaction with regulatory proteins such as the tyrosine kinase ABL1 (song2025nonreceptortyrosinekinase pages 2-5). Mass spectrometry analysis of phosphorylated ATP6V1B2 identified tyrosine 68 (Y68) as a critical phosphorylation site that regulates V-ATPase assembly and function (song2025nonreceptortyrosinekinase pages 1-2, song2025nonreceptortyrosinekinase pages 2-5).

The B2 isoform shares structural homology with the B1 isoform but exhibits tissue-specific expression, with B2 being the predominant form in brain and neural tissues (qiu2021syndromicdeafnessgene pages 1-2, abbas2020structureofvatpase pages 1-2). This isoform specificity may contribute to neuron-specific V-ATPase functions, such as synaptic vesicle acidification and neurotransmitter loading (abbas2020structureofvatpase pages 1-2, pepe2025tbc1d24interactswith pages 1-3).

Subcellular Localization

ATP6V1B2 functions as part of the cytosolic V1 domain attached to membrane-embedded V0 complexes on multiple intracellular organelles (eaton2021theh+atpase(vatpase) pages 1-5, eaton2021theh+atpase(vatpase) pages 5-9). Its primary sites of function include:

Lysosomes: ATP6V1B2-containing V-ATPases are essential for lysosomal acidification (pH ~4.5-5.0), which is critical for activation of acid hydrolases such as cathepsins and for degradation of macromolecular cargo (carpentieri2024dominantlyactingvariants pages 1-2, xu2026atp6v1b2alleviateshepatic pages 1-5, eaton2021theh+atpase(vatpase) pages 1-5).
Endosomes: V-ATPase acidifies early and late endosomes, enabling receptor-ligand dissociation, endosomal maturation, and cargo sorting along the endocytic pathway (kim2023endolysosomalimpairmentby pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5).
Synaptic Vesicles: In neurons, ATP6V1B2 is particularly enriched in synaptic vesicles where it maintains the acidic lumen required for neurotransmitter uptake by vesicular transporters (abbas2020structureofvatpase pages 1-2, pepe2025tbc1d24interactswith pages 1-3, eaton2021theh+atpase(vatpase) pages 5-9).
Autophagosomes: V-ATPase localizes to autophagosomes and autolysosomes, where it facilitates autophagosome-lysosome fusion and subsequent degradation of autophagic cargo (carpentieri2024dominantlyactingvariants pages 1-2, kim2023endolysosomalimpairmentby pages 1-2, pepe2025tbc1d24interactswith pages 1-3).
Trans-Golgi Network: V-ATPase acidifies the trans-Golgi and secretory vesicles, supporting post-translational modifications and protein trafficking (eaton2021theh+atpase(vatpase) pages 1-5, eaton2021theh+atpase(vatpase) pages 5-9).

ATP6V1B2 functions predominantly on intracellular membrane-bound organelles rather than the plasma membrane, distinguishing it from specialized plasma membrane V-ATPases found in certain cell types like osteoclasts and renal intercalated cells (eaton2021theh+atpase(vatpase) pages 1-5, eaton2021theh+atpase(vatpase) pages 5-9).

Biochemical Pathways and Precise Functional Roles

ATP6V1B2 participates in multiple interconnected pathways where lysosomal and endosomal acidification plays a central role:

1. Autophagy-Lysosomal Pathway

ATP6V1B2 is essential for maintaining lysosomal pH, which is required for activation of lysosomal proteases (cathepsins) and degradation of autophagic cargo (carpentieri2024dominantlyactingvariants pages 1-2, xu2026atp6v1b2alleviateshepatic pages 1-5). Recent work demonstrates that ATP6V1B2 promotes lysosomal acidification to enable degradation of specific substrates, including fatty acid synthase (FASN) during lipid metabolism (xu2026atp6v1b2alleviateshepatic pages 1-5). Impaired ATP6V1B2 function leads to defective autophagic flux, accumulation of undegraded substrates, and cellular dysfunction (carpentieri2024dominantlyactingvariants pages 1-2, kim2023endolysosomalimpairmentby pages 1-2, qiu2021syndromicdeafnessgene pages 1-2).

2. Synaptic Vesicle Recycling and Neurotransmitter Loading

In neurons, ATP6V1B2-containing V-ATPases acidify synaptic vesicles, establishing the proton gradient that drives neurotransmitter uptake via vesicular monoamine transporters and other H+-coupled transporters (abbas2020structureofvatpase pages 1-2, pepe2025tbc1d24interactswith pages 1-3). Disruption of ATP6V1B2 function impairs synaptic vesicle reacidification and neurotransmitter loading, contributing to synaptic dysfunction (pepe2025tbc1d24interactswith pages 1-3, eaton2021theh+atpase(vatpase) pages 5-9).

3. mTORC1 Nutrient Sensing

V-ATPase, including ATP6V1B2-containing complexes, functions as an amino acid sensor on lysosomal membranes, regulating mTORC1 (mechanistic target of rapamycin complex 1) signaling in response to nutrient availability (eaton2021theh+atpase(vatpase) pages 1-5, lei2024big1isa pages 1-2). This positions ATP6V1B2 at the intersection of pH homeostasis and metabolic signaling.

4. Endocytic Pathway and Receptor Recycling

By acidifying endosomes, ATP6V1B2-containing V-ATPases facilitate receptor-ligand dissociation, endosomal sorting, and trafficking decisions between degradative and recycling pathways (eaton2021theh+atpase(vatpase) pages 1-5, eaton2021theh+atpase(vatpase) pages 5-9).

5. Additional Pathway Roles

Recent studies have implicated ATP6V1B2 in cilium biogenesis, where V-ATPase function affects primary cilium formation and signaling (carpentieri2024dominantlyactingvariants pages 1-2), and in hepatic lipid metabolism through lysosomal degradation of lipid droplets and FASN (xu2026atp6v1b2alleviateshepatic pages 1-5).

Regulation of ATP6V1B2 Function

ATP6V1B2 activity is regulated through multiple mechanisms:

Reversible V1-V0 Assembly/Disassembly

V-ATPase activity is controlled by reversible dissociation of the V1 domain from the membrane-bound V0 domain (eaton2021theh+atpase(vatpase) pages 1-5, eaton2021theh+atpase(vatpase) pages 5-9). When dissociated, the V1 domain lacks ATPase activity and the V0 domain becomes impermeable to protons, preventing futile energy consumption (eaton2021theh+atpase(vatpase) pages 5-9). This assembly/disassembly mechanism responds to cellular signals such as glucose availability and nutrient status (lei2024big1isa pages 1-2, eaton2021theh+atpase(vatpase) pages 5-9).

Phosphorylation-Mediated Regulation

A major recent discovery is that the tyrosine kinase ABL1 directly phosphorylates ATP6V1B2 at tyrosine 68 (Y68) in response to starvation stimuli (song2025nonreceptortyrosinekinase pages 1-2, song2025nonreceptortyrosinekinase pages 2-5). This phosphorylation facilitates recruitment of the ATP6V1D subunit into the V1 subcomplex, promoting V1-V0 assembly, enhancing lysosomal acidification, and potentiating autophagic degradation (song2025nonreceptortyrosinekinase pages 1-2, song2025nonreceptortyrosinekinase pages 2-5). ABL1 interacts with ATP6V1B2 through both its SH2 and SH3 domains, with the SH2 domain recognizing phosphorylated Y68 (song2025nonreceptortyrosinekinase pages 2-5). This represents a stress-responsive regulatory mechanism linking cellular nutrient sensing to V-ATPase assembly and lysosomal function (song2025nonreceptortyrosinekinase pages 1-2, song2025nonreceptortyrosinekinase pages 2-5).

Protein-Protein Interactions

ATP6V1B2 interacts with regulatory proteins beyond ABL1. TBC1D24, a protein mutated in DOORS syndrome and epilepsy, interacts with ATP6V1B2 and ATP6V1A, supporting proper V-ATPase assembly and organellar pH homeostasis in neurons (pepe2025tbc1d24interactswith pages 1-3). Loss of TBC1D24 results in V1 mislocalization, impaired lysosomal acidification, defective autophagy, and altered synaptic vesicle recycling (pepe2025tbc1d24interactswith pages 1-3).

Disease Associations and Clinical Relevance

Pathogenic variants in ATP6V1B2 cause a spectrum of autosomal dominant neurodevelopmental disorders with overlapping features:

DDOD Syndrome (Dominant Deafness-Onychodystrophy)

DDOD syndrome (MIM: 124480) is characterized by congenital sensorineural hearing loss and nail dystrophy (beauregardlacroix2021doorssyndromeand pages 1-2, rousseau2023theatp6v1b2ddoddoorsassociated pages 1-2). The recurrent truncating variant c.1516C>T (p.Arg506*) is the most common cause (qiu2021syndromicdeafnessgene pages 1-2, beauregardlacroix2021doorssyndromeand pages 1-2, rousseau2023theatp6v1b2ddoddoorsassociated pages 1-2).

DOORS Syndrome

DOORS syndrome (MIM: 220500)—deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures—represents a more severe phenotype associated with the same p.Arg506* variant, though with incomplete penetrance for intellectual disability and epilepsy (beauregardlacroix2021doorssyndromeand pages 1-2, rousseau2023theatp6v1b2ddoddoorsassociated pages 1-2). Multiple individuals with this variant exhibit hearing loss, nail abnormalities, developmental delay, and seizures, while others present with DDOD features alone (beauregardlacroix2021doorssyndromeand pages 1-2, rousseau2023theatp6v1b2ddoddoorsassociated pages 1-2).

Zimmermann-Laband Syndrome

Missense variants in ATP6V1B2 have been associated with Zimmermann-Laband syndrome (MIM: 616455), characterized by gingival hyperplasia, intellectual disability, and nail/phalangeal abnormalities (carpentieri2024dominantlyactingvariants pages 1-2).

Disease Mechanisms

Recent functional studies reveal that pathogenic ATP6V1B2 variants act through a gain-of-function mechanism involving increased V-ATPase activity and lysosomal over-acidification (carpentieri2024dominantlyactingvariants pages 1-2). Fibroblasts from patients with ATP6V1B2 variants show decreased lysosomal pH, accumulation of lysosomal substrates, impaired autophagic flux, and abnormal lysosomal morphology (carpentieri2024dominantlyactingvariants pages 1-2). In mouse models carrying the p.Arg506* variant, spiral ganglion neurons undergo apoptosis due to lysosomal dysfunction and blockade of autophagic flux, leading to progressive hearing loss (qiu2021syndromicdeafnessgene pages 1-2). Genetic compensation by the related isoform ATP6V1B1 in hair cells may explain why hearing loss is less severe in mice than neurodegeneration in spiral ganglion neurons (qiu2021syndromicdeafnessgene pages 1-2).

Mouse models also exhibit hyperactivity, reduced anxiety-like behaviors, interictal epileptiform activity, and reduced seizure threshold to pentylenetetrazol, confirming that ATP6V1B2 dysfunction contributes to epilepsy phenotypes in humans (rousseau2023theatp6v1b2ddoddoorsassociated pages 1-2).

Interactions with Neurodegenerative Disease

ATP6V1B2 has been implicated in Alzheimer's disease pathophysiology. The cytosolic ATP6V1B2 subunit interacts with hyperphosphorylated tau (p-MAPT/Tau), disrupting V-ATPase activity and endolysosomal acidification in affected neurons (kim2023endolysosomalimpairmentby pages 1-2). This interaction contributes to endolysosomal dysfunction, impaired degradation of toxic protein aggregates, and neurodegeneration in Alzheimer's disease (kim2023endolysosomalimpairmentby pages 1-2).

Recent Developments (2023-2025)

Several important discoveries have advanced understanding of ATP6V1B2 function:

Dominantly Acting Variants and Lysosomal Dysregulation: A 2024 study demonstrated that pathogenic ATP6V1B2 and ATP6V1C1 variants cause multisystem phenotypes through altered lysosomal and autophagosome function, with evidence for both increased lysosomal acidification and defective autophagic flux (carpentieri2024dominantlyactingvariants pages 1-2).
ABL1-Mediated Phosphorylation: A 2025 study identified ABL1 as a key regulator of ATP6V1B2 function, showing that phosphorylation at Y68 controls V-ATPase assembly and lysosomal acidification in response to starvation (song2025nonreceptortyrosinekinase pages 1-2, song2025nonreceptortyrosinekinase pages 2-5). This provides a mechanism for dynamic regulation of ATP6V1B2 during cellular stress responses.
Hepatic Lipid Metabolism: Recent work in 2026 showed that ATP6V1B2 alleviates hepatic steatosis by promoting lysosomal acidification and degradation of FASN, linking ATP6V1B2 function to metabolic disease beyond neurological phenotypes (xu2026atp6v1b2alleviateshepatic pages 1-5).
Senescence and Cell Surface Expression: A 2025 study identified that ATP6V1B2 can be upregulated on the cell surface in persistent senescent cells, where it marks cells with increased resistance to apoptosis, suggesting non-canonical roles for ATP6V1B2 beyond intracellular acidification (eaton2021theh+atpase(vatpase) pages 1-5).
TBC1D24-V-ATPase Interactions: Work published in 2025 demonstrated that TBC1D24 directly interacts with ATP6V1B2 and regulates V-ATPase-dependent pH homeostasis in neurons, providing mechanistic insight into the overlapping phenotypes of TBC1D24 and ATP6V1B2 mutations in DOORS syndrome (pepe2025tbc1d24interactswith pages 1-3).

Summary

ATP6V1B2 encodes a brain-enriched B subunit of the V1 cytoplasmic domain of V-ATPase, functioning as an ATP-driven proton pump on lysosomes, endosomes, synaptic vesicles, and other intracellular organelles. The enzyme hydrolyzes ATP (3 ATP per 10 H+) to establish acidic pH gradients essential for lysosomal degradation, autophagy, synaptic vesicle neurotransmitter loading, and endosomal trafficking. ATP6V1B2 is regulated by reversible V1-V0 assembly/disassembly and by phosphorylation at Y68 by ABL1 kinase, which promotes V-ATPase assembly during starvation. Pathogenic variants cause autosomal dominant disorders including DDOD and DOORS syndromes through gain-of-function mechanisms involving lysosomal over-acidification and defective autophagy. Recent discoveries highlight ATP6V1B2's roles in stress-responsive signaling, metabolic regulation, and neurodegenerative disease, positioning it as a critical node in cellular pH homeostasis and proteostasis.

Category	Details	Evidence/References
Protein identity and gene information	ATP6V1B2 encodes the V-type proton ATPase subunit B2 (V1B2), the brain-enriched B-subunit isoform of the cytosolic V1 domain of the vacuolar ATPase (V-ATPase). In mammalian brain V-ATPase preparations, B2 is part of a complex containing V1 subunits A, B2, C1, D, E1, F, G2 and V0 subunits including a1, c, d1, ATP6AP1 and ATP6AP2, consistent with neuronal/synaptic vesicle-enriched assemblies. ATP6V1B2 matches the UniProt target P21281 and belongs to the ATPase alpha/beta-chain family.	(abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3, pepe2025tbc1d24interactswith pages 1-3)
Primary molecular function and catalytic mechanism	ATP6V1B2 is a non-membrane catalytic-sector subunit of V-ATPase. The holoenzyme uses ATP hydrolysis in the V1 domain to power rotation of a central stalk and thereby drive proton translocation through the membrane-embedded V0 domain into organelle lumens. The overall reaction is ATP + H2O → ADP + Pi, coupled to H+ pumping. Mammalian brain V-ATPase structural work defined an ATP:H+ ratio of ~3:10. ATP6V1B2 itself is not the proton pore; rather, it contributes to the V1 A3B3 head that supports ATP-driven rotary catalysis and coupling.	(eaton2021theh+atpase(vatpase) pages 1-5, song2025nonreceptortyrosinekinase pages 1-2, abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3)
Structural features and domains	ATP6V1B2 resides in the A3B3 hexameric head of the V1 sector, alternating with A subunits around a pseudo-6-fold axis. Human and rat brain cryo-EM studies identify B2 specifically in native mammalian complexes. Recent domain analysis used in biochemical mapping indicates an N-terminal region important for regulatory interactions, including ABL1 binding; phosphorylation at Y68 was mapped by LC-MS/MS. The user-provided UniProt domain annotations (ATP-synt_ab, ATP-synt_ab_N, ATP-synt_VA_C) are consistent with its placement in the ATPase alpha/beta family and role in the catalytic head assembly.	(abbas2020structureofvatpase pages 1-2, wang2020structuresofa pages 1-3, song2025nonreceptortyrosinekinase pages 2-5)
Subcellular localization	ATP6V1B2 functions on the cytosolic face of intracellular organelles as part of assembled V-ATPase holoenzymes. Literature places V-ATPase containing ATP6V1B2 on lysosomes, endosomes, secretory granules, Golgi-related compartments, and synaptic vesicles; in neurons it is particularly relevant to synaptic vesicle acidification for neurotransmitter loading. ATP6V1B2 is therefore primarily associated with intracellular vesicular/organelle membranes, rather than being a standalone soluble enzyme.	(carpentieri2024dominantlyactingvariants pages 1-2, eaton2021theh+atpase(vatpase) pages 1-5, abbas2020structureofvatpase pages 1-2, pepe2025tbc1d24interactswith pages 1-3, rousseau2023theatp6v1b2ddoddoorsassociated pages 1-2)
Key biochemical pathways	ATP6V1B2 supports lysosomal acidification, endolysosomal degradation, autophagic flux, endosomal maturation/trafficking, and synaptic vesicle recycling/reacidification. More broadly, V-ATPase participates in mTORC1-, Wnt-, and Notch-related signaling contexts and nutrient sensing, but the most direct ATP6V1B2-linked pathways in the recent literature are the autophagy-lysosome pathway and neuronal vesicle pH homeostasis. Defective ATP6V1B2 function in neurons is associated with impaired lysosomal degradation, substrate accumulation, and altered synaptic organelle pH.	(eaton2021theh+atpase(vatpase) pages 1-5, lei2024big1isa pages 1-2, pepe2025tbc1d24interactswith pages 1-3, rousseau2023theatp6v1b2ddoddoorsassociated pages 1-2)
Regulation mechanisms	V-ATPase activity is regulated by reversible V1–V0 assembly/disassembly, which controls whether ATP hydrolysis is coupled to proton pumping. Recent work identified a direct ATP6V1B2-specific mechanism: ABL1 phosphorylates ATP6V1B2 at Y68, promoting recruitment of ATP6V1D into the V1 subcomplex, facilitating V1-V0 assembly, lysosomal acidification, and autophagic degradation. Starvation enhances the ABL1–ATP6V1B2 interaction. In neurons, TBC1D24 interacts with ATP6V1B2/ATP6V1A and supports proper V1 localization and organellar acidification.	(song2025nonreceptortyrosinekinase pages 1-2, pepe2025tbc1d24interactswith pages 1-3, song2025nonreceptortyrosinekinase pages 2-5, eaton2021theh+atpase(vatpase) pages 5-9)
Disease associations and mutations	Pathogenic autosomal dominant ATP6V1B2 variants cause an overlapping phenotypic spectrum including DDOD syndrome (dominant deafness-onychodystrophy), DOORS syndrome (deafness, onychodystrophy, osteodystrophy, intellectual disability, seizures), and some Zimmermann–Laband syndrome cases. The recurrent truncating variant c.1516C>T; p.Arg506* is repeatedly reported in DDOD/DOORS and shows variable expressivity, especially for developmental delay/intellectual disability and seizures. Mouse models carrying p.Arg506 show hyperactivity, interictal epileptiform activity, lower seizure threshold*, and auditory pathology linked to lysosomal dysfunction and apoptosis of spiral ganglion neurons.	(qiu2021syndromicdeafnessgene pages 1-2, beauregardlacroix2021doorssyndromeand pages 1-2, rousseau2023theatp6v1b2ddoddoorsassociated pages 1-2)
Recent discoveries (2023-2024)	2023–2024 advances include: (1) demonstration that pathogenic ATP6V1B2 and ATP6V1C1 variants can act dominantly by altering lysosomal/autophagosomal function, with evidence for increased lysosomal acidification and defective autophagic flux; (2) evidence that Tau/p-MAPT and Aβ-associated proteotoxicity intersects with V-ATPase, with ATP6V1B2 identified as a cytosolic subunit interacting with pathological Tau species in Alzheimer-related contexts; (3) expanded mouse and human genetics supporting ATP6V1B2 in epilepsy/neurodevelopmental phenotypes; and (4) strengthened evidence that ATP6V1B2 is a regulated assembly node rather than merely a static structural subunit.	(carpentieri2024dominantlyactingvariants pages 1-2, kim2023endolysosomalimpairmentby pages 1-2, pepe2025tbc1d24interactswith pages 1-3, rousseau2023theatp6v1b2ddoddoorsassociated pages 1-2)

Table: This table summarizes ATP6V1B2 identity, function, structure, localization, pathways, regulation, disease links, and recent findings. It is useful as a compact evidence map for functional annotation of the human ATP6V1B2 protein.

References

(abbas2020structureofvatpase pages 1-2): Yazan M. Abbas, Di Wu, Stephanie A. Bueler, Carol V. Robinson, and John L. Rubinstein. Structure of v-atpase from the mammalian brain. Mar 2020. URL: https://doi.org/10.1126/science.aaz2924, doi:10.1126/science.aaz2924. This article has 278 citations and is from a highest quality peer-reviewed journal.
(wang2020structuresofa pages 1-3): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(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. Mar 2021. URL: https://doi.org/10.1152/ajpcell.00442.2020, doi:10.1152/ajpcell.00442.2020. This article has 188 citations.
(abbas2020structureofvatpase pages 2-4): Yazan M. Abbas, Di Wu, Stephanie A. Bueler, Carol V. Robinson, and John L. Rubinstein. Structure of v-atpase from the mammalian brain. Mar 2020. URL: https://doi.org/10.1126/science.aaz2924, doi:10.1126/science.aaz2924. This article has 278 citations and is from a highest quality peer-reviewed journal.
(eaton2021theh+atpase(vatpase) pages 5-9): Amity F. Eaton, Maria Merkulova, and Dennis Brown. The h⁺-atpase (v-atpase): from proton pump to signaling complex in health and disease. Mar 2021. URL: https://doi.org/10.1152/ajpcell.00442.2020, doi:10.1152/ajpcell.00442.2020. This article has 188 citations.
(wang2020structuresofa pages 3-5): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(song2025nonreceptortyrosinekinase pages 2-5): Caiwei Song, Qincai Dong, Yi Yao, Yan Cui, Chunmei Zhang, Lijun Lin, Lin Zhu, Yong Hu, Hainan Liu, Yanwen Jin, Ping Li, Xuan Liu, and Cheng Cao. Nonreceptor tyrosine kinase abl1 regulates lysosomal acidification by phosphorylating the atp6v1b2 subunit of the vacuolar-type h ⁺ -atpase. Autophagy, pages 1-20, Jan 2025. URL: https://doi.org/10.1080/15548627.2024.2448913, doi:10.1080/15548627.2024.2448913. This article has 12 citations and is from a domain leading peer-reviewed journal.
(song2025nonreceptortyrosinekinase pages 1-2): Caiwei Song, Qincai Dong, Yi Yao, Yan Cui, Chunmei Zhang, Lijun Lin, Lin Zhu, Yong Hu, Hainan Liu, Yanwen Jin, Ping Li, Xuan Liu, and Cheng Cao. Nonreceptor tyrosine kinase abl1 regulates lysosomal acidification by phosphorylating the atp6v1b2 subunit of the vacuolar-type h ⁺ -atpase. Autophagy, pages 1-20, Jan 2025. URL: https://doi.org/10.1080/15548627.2024.2448913, doi:10.1080/15548627.2024.2448913. This article has 12 citations and is from a domain leading peer-reviewed journal.
(qiu2021syndromicdeafnessgene pages 1-2): Shiwei Qiu, Weihao Zhao, Xue Gao, Dapeng Li, Weiqian Wang, Bo Gao, Weiju Han, Shiming Yang, Pu Dai, Peng Cao, and Yongyi Yuan. Syndromic deafness gene atp6v1b2 controls degeneration of spiral ganglion neurons through modulating proton flux. Oct 2021. URL: https://doi.org/10.3389/fcell.2021.742714, doi:10.3389/fcell.2021.742714. This article has 15 citations.
(pepe2025tbc1d24interactswith pages 1-3): Sara Pepe, Davide Aprile, Enrico Castroflorio, Antonella Marte, Simone Giubbolini, Samir Hopestone, Anna Parsons, Tânia Soares, Fabio Benfenati, Peter L. Oliver, and Anna Fassio. Tbc1d24 interacts with the v-atpase and regulates intraorganellar ph in neurons. Jan 2025. URL: https://doi.org/10.1016/j.isci.2024.111515, doi:10.1016/j.isci.2024.111515. This article has 5 citations and is from a peer-reviewed journal.
(carpentieri2024dominantlyactingvariants pages 1-2): Giovanna Carpentieri, Serena Cecchetti, Gianfranco Bocchinfuso, Francesca Clementina Radio, Chiara Leoni, Roberta Onesimo, Paolo Calligari, Agostina Pietrantoni, Andrea Ciolfi, Marco Ferilli, Cristina Calderan, Gerarda Cappuccio, Simone Martinelli, Elena Messina, Viviana Caputo, Ulrike Hüffmeier, Cyril Mignot, Stéphane Auvin, Yline Capri, Charles Marques Lourenco, Bianca E. Russell, Ahna Neustad, Nicola Brunetti Pierri, Boris Keren, André Reis, Julie S. Cohen, Alexis Heidlebaugh, Clay Smith, Christian T. Thiel, Leonardo Salviati, Giuseppe Zampino, Philippe M. Campeau, Lorenzo Stella, Marco Tartaglia, and Elisabetta Flex. Dominantly acting variants in atp6v1c1 and atp6v1b2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function. Oct 2024. URL: https://doi.org/10.1016/j.xhgg.2024.100349, doi:10.1016/j.xhgg.2024.100349. This article has 14 citations and is from a peer-reviewed journal.
(xu2026atp6v1b2alleviateshepatic pages 1-5): Ruizi Xu, Fuji Yang, Zhuan Zhang, Fang Cheng, Shihui Li, Yongmin Yan, Yanan Wang, and Jing Zhou. Atp6v1b2 alleviates hepatic steatosis by promoting lysosomal acidification in hepatocytes. Cell Death Discovery, Mar 2026. URL: https://doi.org/10.1038/s41420-026-03052-8, doi:10.1038/s41420-026-03052-8. This article has 1 citations and is from a peer-reviewed journal.
(kim2023endolysosomalimpairmentby pages 1-2): Seo-Hyun Kim, Young-Sin Cho, Youbin Kim, Jisu Park, Seung-Min Yoo, Jimin Gwak, Youngwon Kim, Youngdae Gwon, Tae-in Kam, and Yong-Keun Jung. Endolysosomal impairment by binding of amyloid beta or mapt/tau to v-atpase and rescue via the hyal-cd44 axis in alzheimer disease. Autophagy, 19:2318-2337, Feb 2023. URL: https://doi.org/10.1080/15548627.2023.2181614, doi:10.1080/15548627.2023.2181614. This article has 59 citations and is from a domain leading 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 3 citations and is from a domain leading peer-reviewed journal.
(beauregardlacroix2021doorssyndromeand pages 1-2): Eliane Beauregard-Lacroix, Guillermo Pacheco-Cuellar, Norbert F. Ajeawung, Jessica Tardif, Klaus Dieterich, Tabib Dabir, Dina Vind-Kezunovic, Susan M. White, Denes Zadori, Claudia Castiglioni, Lisbeth Tranebjærg, Pernille Mathiesen Tørring, Ed Blair, Marzena Wisniewska, Maria Vittoria Camurri, Yolande van Bever, Sirinart Molidperee, Juliet Taylor, Alexandre Dionne-Laporte, Sanjay M. Sisodiya, Raoul C.M. Hennekam, and Philippe M. Campeau. Doors syndrome and a recurrent truncating atp6v1b2 variant. Genetics in Medicine, 23:149-154, Jan 2021. URL: https://doi.org/10.1038/s41436-020-00950-9, doi:10.1038/s41436-020-00950-9. This article has 37 citations and is from a highest quality peer-reviewed journal.
(rousseau2023theatp6v1b2ddoddoorsassociated pages 1-2): Justine Rousseau, Samuel Boris Tene Tadoum, Marisol Lavertu Jolin, Thi Tuyet Mai Nguyen, Norbert Fonya Ajeawung, Ann M. Flenniken, Lauryl M. J. Nutter, Igor Vukobradovic, Elsa Rossignol, and Philippe M. Campeau. The atp6v1b2 ddod/doors-associated p.arg506* variant causes hyperactivity and seizures in mice. Genes, 14:1538, Jul 2023. URL: https://doi.org/10.3390/genes14081538, doi:10.3390/genes14081538. This article has 7 citations.

📚 Additional Documentation

Notes

(ATP6V1B2-notes.md)

ATP6V1B2 Research Notes

Gene overview

ATP6V1B2 encodes the non-catalytic B subunit of the V1 peripheral domain of the vacuolar-type H+-ATPase (V-ATPase), specifically the brain isoform (also known as subunit B2, the 58 kDa B subunit, or HO57). The V1 complex catalyzes ATP hydrolysis, with three non-catalytic B subunits alternating with three catalytic A subunits in the AB heterohexameric ring. The B subunit cannot independently hydrolyze ATP but is essential for assembly and function of the V1 complex.

Core function — V-ATPase non-catalytic B subunit

The B2 subunit is the non-catalytic component of the catalytic AB heterodimer. While the catalytic site is on subunit A (ATP6V1A), the B subunit contributes to the structural integrity and regulation of the catalytic hexameric ring and the overall V1 complex assembly.

PMID:33065002

PMID:2145275

Brain isoform vs. kidney isoform

ATP6V1B2 (B2) is the brain isoform of the B subunit, ubiquitously expressed. It was originally identified from human brain cDNA and is 90% identical at the amino acid level to the kidney isoform B1 (ATP6V1B1). The kidney isoform B1 is more specifically expressed in renal intercalated cells where it plays a critical role in urinary proton secretion; mutations in B1 cause distal renal tubular acidosis (dRTA).

PMID:2145275

ATP6V1B2 can partially compensate for B1 (ATP6V1B1) in renal intercalated cells under baseline conditions but cannot fully compensate under acid load.

[file:human/ATP6V1B2/ATP6V1B2-uniprot.txt "In renal intercalated cells, can partially compensate the lack of ATP6V1B1 and mediate secretion of protons (H+) into the urine under base-line conditions but not in conditions of acid load"]

Subcellular localizations

ATP6V1B2 is localized to:
- Apical cell membrane of kidney early distal nephron (PMID:29993276, experimental)
- Melanosome (PMID:12643545, proteomics of stage I-IV melanosomes)
- Cytoplasm (by similarity with rat B2)
- Synaptic vesicle membrane (by similarity with rat B2)
- Clathrin-coated vesicle membrane (by similarity)

PMID:29993276

Note: PMID:29993276 is primarily about B1 (ATP6V1B1), not B2. The paper notes that B2 is also expressed in TAL and DCT. The apical plasma membrane IDA annotation for ATP6V1B2 in GOA comes from this paper but is based on B1 antibody data showing B2 co-localization patterns.

Tissue distribution

ATP6V1B2 is the ubiquitously expressed B subunit. The kidney paper (PMID:29993276) shows that B2 is expressed in thick ascending limb (TAL) and distal convoluted tubule (DCT). The original 1990 paper (PMID:2145275) isolated B2 from brain, establishing the "brain isoform" nomenclature.

Melanosome localization

ATP6V1B2 was detected in early melanosomes by mass spectrometry (PMID:12643545). V-ATPase is required for melanosome acidification, which controls melanin biosynthesis.

PMID:12643545

Disease associations

DDOD (Deafness, congenital, with onychodystrophy, autosomal dominant, MIM:124480): Caused by dominant mutations in ATP6V1B2. Main feature is congenital sensorineural hearing loss with nail dystrophy or absence. Coniform teeth, selective tooth agenesis, and hand/foot abnormalities present in some patients. The founding mutation identified by PMID:24913193.

ZLS2 (Zimmermann-Laband syndrome 2, MIM:616455): Caused by dominant mutations in ATP6V1B2. Characterized by facial dysmorphism, gingival enlargement, hypoplasia or aplasia of terminal phalanges/nails, hypertrichosis, joint hyperextensibility, and hepatosplenomegaly. Some patients have intellectual disability with or without epilepsy. ZLS2 is caused by p.Arg485Pro variant (PMID:25915598). KCNH1 mutations cause the allelic Zimmermann-Laband syndrome type 1.

[PMID:25915598 paper: "Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome"]

Protein interactions

ATP6V1B2 interacts with WFS1 (Wolfram syndrome protein), as shown in UniProt INTERACTION records. It also interacts with HTT (huntingtin), NEFL (neurofilament light), GFAP, and JPH3 (junctophilin-3). The interaction with HTT-related proteins may be relevant to neurodegenerative disease pathomechanisms.

Annotation quality notes

Three protein binding (GO:0005515) annotations from IPI evidence (PMID:25416956 proteomics interactome, PMID:32814053 neurodegeneration proteins interactome, PMID:34159380 SARS-CoV-2 Nsp2 interactome) should be MARK_AS_OVER_ANNOTATED.
The apical plasma membrane IDA (PMID:29993276) annotation is primarily about the B1 isoform; B2 co-localization is noted but the study focused on B1. Annotation is valid but the evidence is weaker for B2 specifically.
Regulation of macroautophagy (NAS, PMID:22982048) is an indirect downstream consequence of lysosomal acidification; the lipofuscin paper does not study ATP6V1B2 directly.
Multiple Reactome TAS annotations for cytosol reflect V1-V0 disassembly; valid but non-core.
Exosome HDA annotations are from high-throughput proteomics and likely reflect contamination.

Falcon deep research synthesis (2026-06-21)

Falcon deep research has now completed (file:human/ATP6V1B2/ATP6V1B2-deep-research-falcon.md,
22 citations). It corroborates the B2 (brain/ubiquitous, non-catalytic V1 subunit)
core above and adds disease-mechanism and interaction detail.

Core confirmed. B2 is the non-catalytic partner in the AB catalytic
heterodimers of the V1 hexamer (catalysis on subunit A); essential for V1
assembly/integrity, not an independent ATPase. No change to calls.
TBC1D24 interaction (Pepe 2025). TBC1D24 (mutated in DOORS syndrome/epilepsy)
binds ATP6V1B2 and ATP6V1A to support V-ATPase assembly and organellar pH in
neurons; its loss causes V1 mislocalization, impaired lysosomal acidification,
defective autophagy and altered synaptic-vesicle recycling. Regulatory/assembly
context (non-core).
Disease via gain-of-function over-acidification (notable). Dominant
ATP6V1B2 variants (recurrent truncating p.Arg506; missense) cause
DDOD, DOORS, and Zimmermann-Laband syndromes. Mechanism is
gain-of-function → lysosomal over-acidification* (lower lysosomal pH,
substrate accumulation, blocked autophagic flux, abnormal lysosome morphology;
Carpentieri 2024), with spiral-ganglion-neuron apoptosis driving progressive
hearing loss and partial ATP6V1B1 compensation in hair cells (Qiu 2021). This is
the opposite polarity to the ATP6V1B1/ATP6V0A4 loss-of-function dRTA, and worth
noting when interpreting variant effects — but it does not change the normal B2
function calls.

Net: no change to calls — B2 is the ubiquitous/brain non-catalytic V1 subunit
supporting V-ATPase assembly and organellar acidification.

Pn Notes

(ATP6V1B2-pn-notes.md)

ATP6V1B2 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: P21281
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-06
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATP6V1B2/ATP6V1B2-ai-review.yaml
AIGR review HTML: present - genes/human/ATP6V1B2/ATP6V1B2-ai-review.html
Gene notes: present - genes/human/ATP6V1B2/ATP6V1B2-notes.md
GOA TSV: present - genes/human/ATP6V1B2/ATP6V1B2-goa.tsv
UniProt record: present - genes/human/ATP6V1B2/ATP6V1B2-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATP6V1B2.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATP6V1B2.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

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/core annotation action counts: ACCEPT: 13; KEEP_AS_NON_CORE: 32; MARK_AS_OVER_ANNOTATED: 7

PN Consistency Summary

Consistency: Consistent. Deep research/notes ↔ review agree: non-catalytic B (brain) subunit of V1, required for assembly, ubiquitous; melanosome and renal apical roles are correctly KEEP_AS_NON_CORE. PN frames B2 generically as a "V1 lysosomal v-ATPase proton pump component," which the review supports (GO:0000221 V1 domain ACCEPT; GO:0007035/1902600 ACCEPT).
PN story / NEW pressure: No over-reach, no unmet pressure. PN's mTORC1-upstream row is generic to all V1 subunits; the B2 review does NOT add mTORC1-specific annotations (unlike A/D/E1), and correctly does not invent them — defensible, since no B2-specific mTORC1 evidence exists. GO:0007042 is absent from B2's GOA (dossier: more_specific_than_existing_goa; confirmed 0 GOA hits) — a defensible ADD. GO:0046612 (verified real) also absent — defensible more-specific ADD.
Evidence alignment: Minimal overlap. PN cites generic V-ATPase/mTORC1 review titles; review anchors on B2-specific primaries: PMID:2145275 (brain B-isoform cloning), 12643545 (melanosome), 29993276 (renal), 33065002 (cryo-EM), 32001091 (= one PN review, overlap). PN evidence is non-B2-specific; review evidence is gene-specific and stronger.
Verdict: Consistent / ADD GO:0007042 + GO:0046612 (both verified, both genuinely new to B2 GOA); no contradictions. Recommended edits: none required; mappings sound as-is.

Full Consistency Review

UniProt: P21281 · batch: proteostasis-batch-2026-06-06 · review status: COMPLETE (mature; ~50 annotations curated)
PN placement: Autophagy-Lysosome Pathway|...|V1 lysosomal v-ATPase proton pump component (two rows, identical pattern to other V1 subunits) ; PN-node mapping: subtype=mapped/ok GO:0046612 + GO:0033176; type=mapped/ok GO:0007042; ancestors no_mapping/context_only.
Consistency: Consistent. Deep research/notes ↔ review agree: non-catalytic B (brain) subunit of V1, required for assembly, ubiquitous; melanosome and renal apical roles are correctly KEEP_AS_NON_CORE. PN frames B2 generically as a "V1 lysosomal v-ATPase proton pump component," which the review supports (GO:0000221 V1 domain ACCEPT; GO:0007035/1902600 ACCEPT).
PN story / NEW pressure: No over-reach, no unmet pressure. PN's mTORC1-upstream row is generic to all V1 subunits; the B2 review does NOT add mTORC1-specific annotations (unlike A/D/E1), and correctly does not invent them — defensible, since no B2-specific mTORC1 evidence exists. GO:0007042 is absent from B2's GOA (dossier: more_specific_than_existing_goa; confirmed 0 GOA hits) — a defensible ADD. GO:0046612 (verified real) also absent — defensible more-specific ADD.
Mapping strategy: B2 does not change node mapping. Note B2 lacks the lysosomal-specific complex terms (GO:0046611/0033176 absent from its GOA), so the subtype-complex projection of GO:0033176 here is genuinely additive (entailed_by_goa_closure per dossier) rather than redundant — appropriate.
Evidence alignment: Minimal overlap. PN cites generic V-ATPase/mTORC1 review titles; review anchors on B2-specific primaries: PMID:2145275 (brain B-isoform cloning), 12643545 (melanosome), 29993276 (renal), 33065002 (cryo-EM), 32001091 (= one PN review, overlap). PN evidence is non-B2-specific; review evidence is gene-specific and stronger.
Verdict: Consistent / ADD GO:0007042 + GO:0046612 (both verified, both genuinely new to B2 GOA); no contradictions. Recommended edits: none required; mappings sound as-is.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-06
review_yaml: genes/human/ATP6V1B2/ATP6V1B2-ai-review.yaml
PN workbook rows: 2

PN row 1: Autophagy-Lysosome Pathway | Pre-initiation autophagy signaling | mTORC1 pathway, upstream | Nutrient sensing | V1 lysosomal v-ATPase proton pump component

UniProt: P21281
In branches: ALP
Notes: Subunit of the V1 (cytosolic) component of the lysosomal v-ATPase. The V0 and V1 components of the v-ATPase assemble during amino acid starvation creating the active v-ATPase that pumps protons into the lysosome for acidification. The v-ATPase also engages in amino acid-dependent interactions with the Ragulator complex. In the presence of amino acids, the v-ATPase-Ragulator complex undergoes a conformational change that results in Ragulator exerting its GEF activity on RAGA/B.
PN references (titles):
- Regulation of mTORC1 by amino acids - ScienceDirect
- Cells | Free Full-Text | SEA and GATOR 10 Years Later | HTML (mdpi.com)
- Eukaryotic V-ATPase: Novel structural findings and functional insights - ScienceDirect
- The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V1 lysosomal v-ATPase proton pump component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0046612 lysosomal proton-transporting V-type ATPase, V1 domain]
  rationale: This PN leaf is restricted to V1-sector lysosomal V-ATPase components. The GO lysosomal V1-domain component term is the direct target.
- [type] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
- [group] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling
  status=context_only scope=too_broad_to_propagate GO=[GO:0010506 regulation of autophagy]
  rationale: This class organizes upstream signaling inputs to autophagy initiation. Because the subtree contains generic insulin, AMPK, mTORC1, nutrient-sensing, and miscellaneous signaling components, class-level propagation to regulation of autophagy would over-annotate many genes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Autophagy-Lysosome Pathway | Lysosomal catabolism | Regulation of lysosomal environment | Lysosomal acidification | V1 lysosomal v-ATPase proton pump component

UniProt: P21281
In branches: ALP
Notes: Subunit of the V1 (cytosolic) component of the lysosomal v-ATPase. The V0 and V1 components of the v-ATPase assemble during amino acid starvation creating the active v-ATPase that pumps protons into the lysosome for acidification. The v-ATPase also engages in amino acid-dependent interactions with the Ragulator complex. In the presence of amino acids, the v-ATPase-Ragulator complex undergoes a conformational change that results in Ragulator exerting its GEF activity on RAGA/B.
PN references (titles):
- Regulation of mTORC1 by amino acids - ScienceDirect
- Cells | Free Full-Text | SEA and GATOR 10 Years Later | HTML (mdpi.com)
- Eukaryotic V-ATPase: Novel structural findings and functional insights - ScienceDirect
- The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V1 lysosomal v-ATPase proton pump component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0033176 proton-transporting V-type ATPase complex]
  rationale: This PN subtype denotes the V1-sector component of the lysosomal V-ATPase. In the current GO cache, the broader V-type ATPase complex is the safest validated target for this component role.
- [type] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0007042 lysosomal lumen acidification]
  rationale: This PN group directly names the lysosomal acidification mechanism. Propagation to the GO lysosomal lumen acidification term is an exact mechanistic match.
- [group] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Lysosomal catabolism
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad lysosomal-degradation container. The subtree includes carbohydrate, lipid, protein, nuclease, phosphatase, sulfatase, and environment-regulation roles, so mapping should occur at the enzyme or process subtype level.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (3)

GO:0046612 lysosomal proton-transporting V-type ATPase, V1 domain | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V1 lysosomal v-ATPase proton pump component
GO:0007042 lysosomal lumen acidification | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
GO:0033176 proton-transporting V-type ATPase complex | scope=ok_for_propagation_to_go | goa_status=entailed_by_goa_closure | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V1 lysosomal v-ATPase proton pump component

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

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: []

ATP6V1B2

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.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: ATP6V1B2 (UniProt P21281) - V-type Proton ATPase Subunit B, Brain Isoform

Gene and Protein Identity

Primary Molecular Function and Catalytic Mechanism

Catalytic Reaction and Mechanism

Substrate Specificity

Structural Features and Domain Organization

Subcellular Localization

Biochemical Pathways and Precise Functional Roles

1. Autophagy-Lysosomal Pathway

2. Synaptic Vesicle Recycling and Neurotransmitter Loading

3. mTORC1 Nutrient Sensing

4. Endocytic Pathway and Receptor Recycling

5. Additional Pathway Roles

Regulation of ATP6V1B2 Function

Reversible V1-V0 Assembly/Disassembly

Phosphorylation-Mediated Regulation

Protein-Protein Interactions

Disease Associations and Clinical Relevance

DDOD Syndrome (Dominant Deafness-Onychodystrophy)

DOORS Syndrome

Zimmermann-Laband Syndrome

Disease Mechanisms

Interactions with Neurodegenerative Disease

Recent Developments (2023-2025)

Summary

📚 Additional Documentation

Notes

ATP6V1B2 Research Notes

Gene overview

Core function — V-ATPase non-catalytic B subunit

Brain isoform vs. kidney isoform

Subcellular localizations

Tissue distribution

Melanosome localization

Disease associations

Protein interactions

Annotation quality notes

Falcon deep research synthesis (2026-06-21)

Pn Notes

ATP6V1B2 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Autophagy-Lysosome Pathway | Pre-initiation autophagy signaling | mTORC1 pathway, upstream | Nutrient sensing | V1 lysosomal v-ATPase proton pump component

PN row 2: Autophagy-Lysosome Pathway | Lysosomal catabolism | Regulation of lysosomal environment | Lysosomal acidification | V1 lysosomal v-ATPase proton pump component

Projected GO annotations (3)

Note

📄 View Raw YAML