STRUCTURAL CHANGES AND SIGNALLING IN CALCIUM REGULATORS

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The objective is to understand the structural basis for calcium regulation in cellular processes. It is proposed to study the structures of calcium regulating proteins in different functional states, principally using small angle solution scattering and spectroscopic techniques such as Fourier transform infra-red spectroscopy (FTIR) and circular dichroism (CD). Specifically, the work will focus on the class of structurally related, though functionally diverse, regulatory proteins that includes calmodulin, troponin C and parvalbumin. Initial studies have concerned the effects of the solution environment on the calmodulin and troponin C structures. Future work will be directed more toward the interactions of these proteins with other components in their biochemical systems. In particular, we wish to: o further study the influence of the solution environment on the structures of troponin C and calmodulin; o investigate the structural and functional consequences of covalent modifications of calmodulin; o study the interactions of extrinsic and intrinsic calmodulin with the subunits of phosphorylase kinase; o study the interactions of calmodulin with the calmodulin binding domain of myosin light chain kinase and related peptides. Small angle solution scattering will be used to characterize the overall shapes and interactions of components of these systems in different states of activation. FTIR and CD spectroscopy will be used to evaluate secondary structure content, and, in particular, to monitor changes in secondary structure that accompany changes in functional state. Interpretation of the low resolution structural information that is obtained using these techniques will be greatly enhanced by the availability of high resolution crystallographic data on the proteins. The long term goal is to understand the molecular mechanism for calcium regulation.