The mechanics of calcium transport.
With the recent atomic models for the sarcoplasmic reticulum Ca(2+)-ATPase in the Ca(2+)-bound state, the Ca(2+)-free, thapsigargin-inhibited state, and the Ca(2+)-free, vanadate-inhibited state, we are that much closer to understanding and animating the Ca(2+)-transport cycle. These "snapshots" of the Ca(2+)-transport cycle reveal an impressive breadth and complexity of conformational change. The cytoplasmic domains undergo rigid-body movements that couple the energy of ATP to the transport of Ca2+ across the membrane. Large-scale rearrangements in the transmembrane domain suggest that the Ca(2+)-binding sites may alternately cease to exist and reform during the transport cycle. Of the three cytoplasmic domains, the actuator (A) domain undergoes the largest movement, namely a 110 degrees rotation normal to the membrane. This domain is linked to transmembrane segments M1-M3, which undergo large rearrangements in the membrane domain. Together, these movements are a main event in Ca2+ transport, yet their significance is poorly understood. Nonetheless, inhibition or modulation of Ca(2+)-ATPase activity appears to target these conformational changes. Thapsigargin is a high-affinity inhibitor that binds to the M3 helix near Phe256, and phospholamban is a modulator of Ca(2+)-ATPase activity that has been cross-linked to M2 and M4. The purpose of this review is to postulate roles for the A domain and M1-M3 in Ca2+ transport and inhibition.
Young
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Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G2H7, Canada. hyoung@ualberta.ca
Stokes
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DL
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology
D004791:Enzyme Inhibitors; D019284:Thapsigargin; D000255:Adenosine Triphosphate; D000252:Calcium-Transporting ATPases; D002118:Calcium