Ca2+ポンプの分子作動機構：部位特異的変異及びリン酸化中間体アナログの開発と構造解析による理解

概要

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Sarco(endo)plasmic reticulum Ca2+-ATPase is a representative member of P-type cation transporting ATPases and catalyzes Ca2+ transport coupled with ATP hydrolysis. The ATPase possesses three cytoplasmic domains (N, P, and A) and ten transmembrane helices (M1-M10). Ca2+ binding at the transport sites in the transmembrane domain activates the ATPase and then the catalytic aspartate is auto-phosphorylated to form the phosphorylated intermediate (EP). Structural and functional studies have shown that, during the isomerization of EP in the Ca2+ transport cycle, large motions of the three cytoplasmic domains take place, which then rearranges the transmembrane helices thereby destroying the Ca2+ binding sites, opening the lumenal gate, and thus releasing the Ca2+ into lumen. Stable structural analogues for the Ca2+-occluded and -released states of phosphorylated intermediates and for the transition and product states of the phosphorylation and dephosphorylation reactions were developed for biochemical and atomic-level structural studies to reveal the coupled changes in the catalytic and transport sites. Mutation studies identified the residues and structural regions essential for the structural changes and Ca2+ transport function. Genetic dysfunction of Ca2+-ATPase causes various isoform-specific diseases. In this manuscript, recent understanding of the Ca-ATPase will be reviewed.
社団法人　日本薬学会の論文