Vacuolar-type H+-ATPase c-ring (V-ATPase c-ring)

The Vacuolar-type H+-ATPase (V-ATPase) c-ring is a critical component of the V0 domain of the V-ATPase enzyme complex, a highly conserved rotary motor that functions as an ATP-dependent proton pump (PMID: 16691478). Composed primarily of multiple copies of the 16 kDa proteolipid subunit (encoded by the ATP6V0C gene), the c-ring forms the transmembrane rotor that facilitates the translocation of protons across membranes (UniProt P27449). This process is essential for the acidification of various intracellular organelles, such as lysosomes, endosomes, and the Golgi apparatus, which in turn regulates protein sorting, receptor-mediated endocytosis, and autophagy (GeneCards ATP6V0C). In specialized cells like osteoclasts, V-ATPases are also found on the plasma membrane, where they acidify the extracellular environment to facilitate bone resorption (PMID: 26020805). Dysregulation or overexpression of the V-ATPase c-ring is implicated in several diseases, most notably cancer and osteoporosis. In tumors, increased V-ATPase activity promotes an acidic microenvironment that favors invasion, metastasis, and resistance to chemotherapy (PMID: 26020805). Mutations in the ATP6V0C gene have also been linked to neurodevelopmental disorders and epilepsy (Frontiers in Molecular Neuroscience, 2022). Because of its central role in these pathologies, the c-ring has become a significant therapeutic target. Potent natural product inhibitors like bafilomycin and concanamycin bind directly to the c-ring to block its rotation and proton pumping activity (PMID: 16691478). However, the ubiquitous nature of V-ATPases presents a major challenge for drug development, as systemic inhibition can lead to significant toxicity, necessitating the development of more selective or localized therapeutic strategies (PMID: 33403312).

Other names

V-ATPase V0 domain subunit cATP6V0CATP6CVPPCV-type proton ATPase 16 kDa proteolipid subunitATPase H+ transporting V0 subunit cV-ATPase 16 kDa proteolipid subunit

Inhibition of the rotary mechanism of the V-ATPase by binding to the c-ring, thereby blocking proton translocation and organelle acidification.