3.A.3.3.6
Plamsa membrane H⁺-ATPase, Pma1 (pumps protons out of the cell to generate a membrane potential and regulate cytosolic pH) (Liu et al., 2006; Petrov, 2009). TMSs 4,5,6 and 8 comprise the H⁺ pathway where essential and important residues have been identified (Miranda et al., 2010). Residues in the loop between TMSs 5 and 6 play roles in protein stability, function, and insertion (Petrov 2015).  Pma1 interacts with the plamsa membrane Cch1/Mid1 (1.A.1.11.10) to regulate its activity by influencing the membrane potential (Cho et al. 2016).  Asp739 and Arg811 are important residues for the biogenesis and function of the enzyme as H⁺ transport determinants (Petrov 2017). Pma1, is a P3A-type ATPase and the primary protein component of the membrane compartment of Pma1 (MCP). Like other plasma membrane H⁺-ATPases, Pma1 assembles and functions as a hexamer, a property unique to this subfamily of P-type ATPases. It has been unclear how Pma1 organizes the yeast membrane into MCP microdomains, or why it is that Pma1 needs to assemble into a hexamer to establish the membrane electrochemical proton gradient. Zhao et al. 2021 reported a high-resolution cryo-EM study of native Pma1 hexamers embedded in endogenous lipids. The Pma1 hexamer encircles a liquid-crystalline membrane domain composed of 57 ordered lipid molecules. The Pma1-encircled lipid patch structure likely serves as the building block of the MCP. At pH 7.4, the carboxyl-terminal regulatory α-helix binds to the phosphorylation domains of two neighboring Pma1 subunits, locking the hexamer in the autoinhibited state. The regulatory helix becomes disordered at lower pH, leading to activation of the Pma1 hexamer. The activation process is accompanied by a 6.7 A downward shift and a 40 degrees rotation of transmembrane helices 1 and 2 that line the proton translocation path. The conformational changes enabled the authors to propose a detailed mechanism for ATP-hydrolysis-driven proton pumping across the plasma membrane (Zhao et al. 2021). An ER-accumulated mutant of yeast Pma1 causes membrane-related stress to induce the unfolded protein response (Phuong et al. 2023).