Structural and functional understanding of disease-associated mutations in V-ATPase subunit a1 and other isoforms

The vacuolar-type ATPase (V-ATPase) is a multisubunit protein composed of the cytosolic adenosine triphosphate (ATP) hydrolysis catalyzing V 1 complex, and integral membrane o , responsible for proton translocation. largest subunit a, enables translocation upon ATP hydrolysis, mediated by complex. Four known isoforms (a1–a4) are expressed in different cellular locations. Subunit a1 (also as a1), neural isoform, strongly neurons encoded ATP6V0A1 gene. Global knockout this gene mice causes embryonic lethality, whereas pyramidal neuron-specific resulted neuronal cell death with impaired spatial learning memory. Recently reported, de novo biallelic mutations human impair autophagic lysosomal activities, contributing to developmental epileptic encephalopathies (DEE) early onset progressive myoclonus epilepsy (PME). heterozygous R740Q mutation most recurrent variant reported cases DEE. Homology studies suggest R740 deprotonates protons from specific glutamic acid residues c, highlighting its importance overall V-ATPase function. In paper, we discuss structure mechanism V-ATPase, emphasizing how can lead dysfunction neurodevelopmental disorders, non-neural isoforms, a2–a4, also various genetic diseases. Given growing discovery disease-causing variants function pump-based regulator intracellular organelle pH, multiprotein complex warrants further investigation.