ATP6V1A encodes the catalytic A subunit (V1A, also known as the 70 kDa or alpha subunit) of the V1 peripheral domain of the vacuolar-type H+-ATPase (V-ATPase). The V1 domain is the ATP-hydrolyzing sector of the proton pump; subunit A forms the catalytic AB heterodimer (three copies per V1 hexamer) together with subunit B and contains the nucleotide-binding/hydrolysis site.
The primary role of ATP6V1A is to hydrolyze ATP and power proton translocation across the membranes of intracellular organelles (lysosomes, endosomes, Golgi, secretory vesicles) and, in specialized cells, the plasma membrane.
The complete human V-ATPase structure was determined by cryo-EM (Wang et al. 2020, PMID:33065002). The V1 complex consists of three catalytic AB heterodimers forming a heterohexamer, three EG peripheral stalks, one central rotor (subunits D and F), and regulatory subunits C and H. ATP hydrolysis by subunit A (the catalytic subunit) at the AB interface drives rotation of the central rotor, which in turn drives proton translocation through the V0 ring.
The V-ATPase (including the V1A subunit) is required for amino acid sensing by mTORC1 at the lysosome surface. This is mediated through interactions of the V1 domain with the Ragulator complex in an amino acid-sensitive manner, allowing mTORC1 recruitment and activation.
V-ATPase function (including ATP6V1A) is required for intracellular iron homeostasis. Loss of V-ATPase activity leads to intracellular iron depletion, reduced PHD activity, and HIF1A stabilization under aerobic conditions.
V-ATPase acidification of lysosomes is required for autophagic flux. The annotation linking V-ATPase to regulation of macroautophagy comes from a study on lipofuscin formation (PMID:22982048), where lysosomal activity inhibition was a secondary experimental variable.
ATP6V1A interacts with WFS1 (Wolfram syndrome 1 protein) in secretory granules in neuroblastoma cells. WFS1 regulates the expression and stability of the V1A subunit.
ARCL2D (autosomal recessive cutis laxa type 2D, MIM:617403): Caused by biallelic loss-of-function variants in ATP6V1A. Manifests as skin wrinkling, large fontanelle, facial appearance, hypotonia, cardiovascular and neurologic involvement.
IECEE3 (infantile/early childhood epileptic encephalopathy 3, MIM:618012): Caused by dominant (de novo) heterozygous missense mutations. De novo mutations p.Pro27Arg, p.Asp100Tyr, p.Asp349Asn, p.Asp371Gly identified in patients with developmental encephalopathy with epilepsy.
ATP6V1A is a peripheral membrane protein of the V1 domain. It is found at lysosomal membrane (is_active_in), secretory granules (co-localizes with WFS1 in neuroblastoma), and the cytosol (V1 domain can reversibly dissociate from V0). Presence in cytoplasm reflects the known regulated V1-V0 disassembly mechanism (e.g., under nutrient deprivation). Some GO annotations cite plasma membrane localization from specific cell types (e.g., osteoclasts). Extracellular exosome annotations are from high-throughput proteomics studies.
ATP6V1A facilitates Rabies virus uncoating in endosomes through interaction with the viral M protein. This is a host-pathogen interaction rather than a core cellular function.
Falcon deep research has now completed (file:human/ATP6V1A/ATP6V1A-deep-research-falcon.md,
37 citations). It strongly corroborates the catalytic-A-subunit core above and
adds regulatory and disease detail.
Net: no change to calls — ATP6V1A is the V1 catalytic (ATP-hydrolyzing) subunit
powering organellar acidification.