Flexible P-type ATPases interacting with the membrane

Cation pumps and lipid flippases of the P-type ATPase family maintain electrochemical gradients and asymmetric lipid distributions across membranes, and offer significant insight of protein:membrane interactions. The sarcoplasmic reticulum Ca2+-ATPase features flexible and adaptive interactions with the surrounding membrane, while the Na+,K+-ATPase complex is modulated by membrane components and a role for the γ-subunit as a stabilizer of a specific lipid interaction with the α-subunit has been proposed. The first crystal structure of a heavy-metal transporting ATPase shows a markedly amphipathic helix at the cytoplasmic membrane surface, highlighting this structure as a general motif of all P-type ATPases although with specialization to different membranes. Residues of central importance for the lipid flippase activity of the P4-type ATPase subfamily have been pinpointed by mutational studies, but the transport pathway and mechanism remain unknown.

► Lipids and ligands bound in the membrane environment are illustrated on SERCA and NA+,K+-ATPase structures. ► SERCA show a flexible and adaptive interaction with the surrounding membrane. ► Na+,K+-ATPase γ-subunit stabilizes specific protein–lipid interaction. ► Amphipathic helix at cytoplasmic surface is a conserved structural element, but found in different structural contexts. ► Residues with central importance for lipid transport in P4-type ATPases map to the classical ion pathway but may also reflect intramolecular control.