Calmodulin Mediated Disorder-to-Order Transitions: Calcineurin as a Model System

In recent years many intrinsically disordered proteins {lOP's) have been identified in numerous biologically important systems (1). It is not clear is why protein disorder is so common. A number of hypotheses have been advanced, one of which is that disorder-to-order transitions can be used to regulate protein function. Calmodulin (CaM) is a very abundant, highly conserved calcium sensor known to regulate the functions of numerous essential proteins (2, 3). It was recently proposed that many of the CaM binding sites within target proteins are located in intrinsically disordered regions and that some of these undergo disorder-to-order transitions upon CaM binding (4). Calcineurin (CaN) is a highly-conserved serine/threonine phosphatase that is activated when bound by CaM. CaN is a central player in a number of vital processes that include T cell activation, cardiac growth, ancl regulation of neuronal communication. Upon binding of CaM to the regulatory domain of CaN, a conformational change is induced that results in activation of the enzyme. Experimental! data suggests the regulatory domain of CaN is disordered in the inactive enzyme, and that it undergoes a disorder-to-order transition upon CaM binding. The goal of this proposal is to cbaracterize the physical nature of this disorder-to-order transition. We are using CaN as a model system in our studies of CaMmediated disorder-to-order transitions that regulate biological activity.