With the recent atomic models for the sarcoplasmic reticulum Ca2+-ATPase in the Ca2+-bound state, the Ca2+-free, thapsigargin-inhibited state, and the Ca2+-free, vanadate-inhibited state, we are that much closer to understanding and animating the Ca2+-transport cycle. These „snapshots” of the Ca2+-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 Ca2+-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° 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 Ca2+-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 Ca2+-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.
The Journal of Membrane Biology – Springer Journals
Published: Jan 1, 2004
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