3.A.2.2.4
The 14 subunit vacuolar H⁺-ATPase, V₁/V₀, has been implicated in various human diseases including osteopetrosis, renal tubule acidosis, and cancer (Hinton et al., 2009).  The transmembrane enzyme, Ribonuclease kappa, RNASEK (137 aas; 2 TMSs; UniProt acc# Q6P5S7), closely associates with the V-ATPase and is required for its function; its loss prevents the early events of endocytosis and the replication of multiple pathogenic viruses (Perreira et al. 2015).  Cryo-EM allowed the construction of an atomic model, defining the enzyme's ATP:proton ratio as 3:10 and revealing a homolog of yeast subunit f in the membrane region, which appeared to be RNAseK (Abbas et al. 2020). The c ring encloses the transmembrane anchors for cleaved ATP6AP1/Ac45 and ATP6AP2/PRR, the latter of which is the (pro)renin receptor that, in other contexts, is involved in both Wnt signaling and the renin-angiotensin system that regulates blood pressure. This structure shows how ATP6AP1/Ac45 and ATP6AP2/PRR enable assembly of the enzyme's catalytic and membrane regions (Abbas et al. 2020). V-ATPase inhibitors, concanamycin and indole pentadiene, inhibit the enzyme by entry through the lipid membrane (Páli et al. 2004). ATP6V1, subunit H deficiency impairs glucose tolerance by augmenting endoplasmic reticulum stress in high fat diet fed mice (Yang et al. 2022). Defective lysosomal acidification provides a prognostic marker and therapeutic target for neurodegenerative diseases (Lo and Zeng 2023).  Variants in ATP6V1B2 are related to a heterogeneous group of multisystemic disorders sometimes associated with variable neurological involvement, including developmental epileptic encephalopathies (Amore et al. 2023). The subunit, ATP6V0A4 is a potential biomarker in renal cell carcinoma (Xu et al. 2023). The V-ATPase complex component RNAseK is required for lysosomal hydrolase delivery and autophagosome degradation (Makar et al. 2024).  The increased expression of V-ATPase following bafilomycin A1 suggests a critical role of the proton pump in glioblasstoma stem components (Giambra et al. 2024).