Evolutionary Prevalence of the Electrostatic Switch Mechanism in P-type ATPases

P-type ATPases are active transporter enzymes that maintain ion electrochemical gradients for functions such as muscle contraction, kidney function, digestion, and nerve signalling. The dysfunction of these ATPases has been linked to several neurological, cardiovascular, and metabolic disorders. An electrostatic switch mechanism (ESM) has been hypothesised to be involved in the regulation of the sodium-potassium pump (Na⁺,K⁺-ATPase) and the gastric proton pump (H⁺,K⁺-ATPase). An analysis of primary and tertiary protein structures suggests a potentially higher prevalence of the ESM in human P-type ATPases than previously thought. Evidence for the ESM was found on the N-terminus for the P1B, and P2C subfamilies of P-type ATPases, and on the C-terminus for the P2A and P5 subfamilies. In the case of the P4 family, evidence for the ESM was found on the N-terminus for some subfamilies and on the C-terminus for others. Evidence for the ESM has been identified in P-type ATPase subfamilies distributed in separate lineages of the phylogenetic tree, suggesting that the ESM evolved multiple times independently.