On Allosteric Modulation of P-Type Cu+-ATPases

P-type ATPases perform active transport of various compounds across biological membranes and are crucial for ion homeostasis and the asymmetric composition of lipid bilayers. Although their functional cycle share principles of phosphoenzyme intermediates, P-type ATPases also show subclass-specific sequence motifs and structural elements that are linked to transport specificity and mechanistic modulation. Here we provide an overview of the Cu+-transporting ATPases (of subclass PIB) and compare them to the well-studied sarco(endo)plasmic reticulum Ca2+-ATPase (of subclass PIIA). Cu+ ions in the cell are delivered by soluble chaperones to Cu+-ATPases, which expose a putative “docking platform” at the intracellular interface. Cu+-ATPases also contain heavy-metal binding domains providing a basis for allosteric control of pump activity. Database analysis of Cu+ ligating residues questions a two-site model of intramembranous Cu+ binding, and we suggest an alternative role for the proposed second site in copper translocation and proton exchange. The class-specific features demonstrate that topological diversity in P-type ATPases may tune a general energy coupling scheme to the translocation of compounds with remarkably different properties. [Display omitted] ► Important structural differences are described between Ca2+-ATPases and Cu+-ATPases. ► Allosteric function of the heavy-metal binding domain is suggested. ► A proposed second site in the membrane is compared to a database of copper-coordinating residues and found to be unlikely as a copper-binding site. ► The second site might be implicated as a putative site for proton exchange.