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V-type ATPases are multi-protein complexes, which acidify cellular compartments in eukaryotes. They pump protons against an ion gradient, driven by a mechano-chemical framework that exploits ATP hydrolysis as an energy source. This process drives rotation of the so-called c-ring, a membrane embedded complex in the V-domain of the V-type ATPase, resulting in translocation of protons across the membrane. One way in which the enzyme is regulated is by disassembly and reassembly of the V-domain with the V-domain, which inactivates and reactivates the enzyme, respectively. Recently, structural data for the isolated V-domain from S. cerevisiae in an inactivated state were reported, suggesting the location of previously unobserved proton access pathways within the cytoplasmic and luminal compartments of the stator subunit a in V. However, the structural rationale for this inactivation remained unclear. In this study, the water accessibility pathway at the cytoplasmic side is confirmed, and novel insights into the role of the luminal channel with respect to the inactivation mechanism are obtained, using atomic-resolution molecular dynamics simulations. The results show that protonation of the key-glutamate, located in the c-ring of the V-domain, and facing the luminal compartment is preserved, when residing in the V-depleted state. Maintaining the protonation of this essential glutamate is necessary to lock the luminal channel in the inactive, solvent-free state. Based on these theoretical observations and previous experimental results, a model of the proton translocation mechanism in the V-domain from V-type ATPases is proposed.
This article was published in the following journal.
Name: Biochimica et biophysica acta. Biomembranes
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