Calcineurin: Form and function

Calcineurin is a eukaryotic Ca2+- and calmodulin-dependent serine/threonine protein phosphatase. It is a heterodimeric protein consisting of a catalyt ic submit calcineurin A, which contains an active site dinuclear metal cent er, and a tightly associated, myristoylated, Ca2+-binding submit, calcineur in B. The primary sequence of both submits and heterodimeric quaternary str ucture is highly conserved from yeast to mammals. As a serine/threonine pro tein phosphatase, calcineurin participates in a number of cellular processe s and Ca2+- dependent signal transduction pathways. Calcineurin is potently inhibited by immunosuppressant drugs, cyclosporin A and FK506, in the pres ence of their respective cytoplasmic immunophilin proteins, cyclophilin and FK506-binding protein. Many studies have used these immunosuppressant drug s and/or modern genetic techniques to disrupt calcineurin in model organism s such as yeast, filamentous fungi, plants, vertebrates, and mammals to exp lore its biological function. Recent advances regarding calcineurin structu re include the determination of its three-dimensional structure. In additio n, biochemical and spectroscopic studies are beginning to unravel aspects o f the mechanism of phosphate ester hydrolysis including the importance of t he dinuclear metal ion cofactor and metal ion redox chemistry, studies whic h may lead to new calcineurin inhibitors. This review provides a comprehens ive examination of the biological roles of calcineurin and reviews aspects related to its structure and catalytic mechanism.