The sarcoplasmic Ca2+- ATPase : design of a perfect chemi- osmotic pump

The sarcoplasmic (SERCA 1a) Ca2+-ATPase is a membrane proteinabundantly present in skeletal mucles where it functions as an indispensable component ofthe excitation–contraction coupling, being at the expense of ATP hydrolysis involved inCa2+/H+exchange with a high thermodynamic efficiency across the sarcoplasmic reticulummembrane. The transporter serves as a prototype of a whole family of cation transporters, theP-type ATPases, which in addition to Ca2+transporting proteins count Na+,K+-ATPase andH+,K+-, proton- and heavy metal transporting ATPases as prominent members. The abilityin recent years to produce and analyze at atomic (2 3–3 A˚) resolution 3D-crystals ofCa2+-transport intermediates of SERCA 1a has meant a breakthrough in our understanding ofthe structural aspects of the transport mechanism. We describe here the detailed constructionof the ATPase in terms of one membraneous and three cytosolic domains held together by acentral core that mediates coupling between Ca2+-transport and ATP hydrolysis. Duringturnover, the pump is present in two different conformational states, E1 and E2, with apreference for the binding of Ca2+and H+, respectively. We discuss how phosphorylated andnon-phosphorylated forms of these conformational states with cytosolic, occluded or luminallyexposed cation-binding sites are able to convert the chemical energy derived from ATPhydrolysis into an electrochemical gradient of Ca2+across the sarcoplasmic reticulummembrane. In conjunction with these basic reactions which serve as a structural framework forthe transport function of other P-type ATPases as well, we also review the role of the lipidphase and the regulatory and thermodynamic aspects of the transport mechanism