V-type proton ATPase subunit S1

ATP6AP1 encodes V-type proton ATPase subunit S1, an accessory component of the vacuolar H+-ATPase complex (UniProt: Q15904). This protein guides V-ATPase into specialized subcellular compartments including secretory vesicles and osteoclast ruffled borders, regulating luminal acidification and membrane trafficking. It also participates in intracellular iron homeostasis by modulating HIF1A hydroxylation in aerobic conditions.

ATP6AP1 is implicated in Immunodeficiency 47 (IMD47), an X-linked recessive disorder characterized by hypogammaglobulinemia, recurrent infections, and abnormal protein glycosylation, with neurologic manifestations including seizures and behavioral abnormalities in some patients (UniProt: Q15904).

In Alzheimer's Disease, ATP6AP1 is significantly downregulated in post-mortem AD brain relative to age-matched controls (Chaparral AD proteomics), with a mean log2 fold-change of −0.76 across subcellular fractions. This reduction may reflect impaired vesicular acidification and membrane dynamics pathways relevant to amyloid and tau metabolism in AD neurodegeneration.