Structural Basis Of Dilated Cardiomyopathy

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DESCRIPTION (provided by applicant): The overall goal of my research program is to determine the molecular and structural determinants of dilated cardiomyopathy (DCM), the leading cause for heart failure (HF) worldwide. Three major groups of cardiac proteins are involved in DCM: cytoskeletal, nuclear, and sarcomeric. Our group focuses on the study of mutations occurring in phospholamban (PLN), a membrane protein involved in calcium transport in the sarcoplasmic reticulum (SR). PLN binds and inhibits the SR Ca-ATPase (SERCA), regulating heart diastole. PLN phosphorylation at Ser16 by protein kinase A (PKA) reverses the inhibitory effects, constituting the primary response to b-adrenergic stimulation in the heart. Disruptions in the phosphorylation cycle progress to HF. The R9C mutation (PLNR9C) and R14 deletion (PLNR14del), both located in the PLN cytoplasmic domain, prevent PLN phosphorylation and lead to DCM via an unknown mechanism. Using a battery of biochemical, molecular biology, and spectroscopic methods, we will characterize the structural and dynamic effects of these mutations in the formation of the PKA/PLN complex and link them to their cardiotoxicity. Specifically, we plan to decipher the PLN recognition and phosphorylation mechanisms by the kinase in the presence and absence of these deadly mutations. Moreover, we will elucidate the role of lipid membranes and spatial localization via myristoylation in the phosphorylation process. These studies will set the groundwork for understanding the physiology and pathophysiology of phosphorylation signaling in the heart.