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.
Dilated cardiomyopathy (DCM) is the leading cause for heart failure (HF) worldwide. This proposal seeks to elucidate the molecular determinants for DCM using biophysical, biochemical, and molecular biology approaches. Understanding the genesis of the disease at the atomic level will help translate this knowledge into molecular design of new therapeutic approaches to counteract HF.
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|Cembran, Alessandro; Kim, Jonggul; Gao, Jiali et al. (2014) NMR mapping of protein conformational landscapes using coordinated behavior of chemical shifts upon ligand binding. Phys Chem Chem Phys 16:6508-18|
|Gopinath, T; Mote, Kaustubh R; Veglia, Gianluigi (2013) Sensitivity and resolution enhancement of oriented solid-state NMR: application to membrane proteins. Prog Nucl Magn Reson Spectrosc 75:50-68|
|Veglia, Gianluigi; Cembran, Alessandro (2013) Role of conformational entropy in the activity and regulation of the catalytic subunit of protein kinase A. FEBS J 280:5608-15|
|Chao, Fa-An; Shi, Lei; Masterson, Larry R et al. (2012) FLAMEnGO: a fuzzy logic approach for methyl group assignment using NOESY and paramagnetic relaxation enhancement data. J Magn Reson 214:103-10|
|Gopinath, T; Veglia, Gianluigi (2012) Dual acquisition magic-angle spinning solid-state NMR-spectroscopy: simultaneous acquisition of multidimensional spectra of biomacromolecules. Angew Chem Int Ed Engl 51:2731-5|
|Verardi, Raffaello; Traaseth, Nathaniel J; Shi, Lei et al. (2011) Probing membrane topology of the antimicrobial peptide distinctin by solid-state NMR spectroscopy in zwitterionic and charged lipid bilayers. Biochim Biophys Acta 1808:34-40|
|Ha, Kim N; Masterson, Larry R; Hou, Zhanjia et al. (2011) Lethal Arg9Cys phospholamban mutation hinders Ca2+-ATPase regulation and phosphorylation by protein kinase A. Proc Natl Acad Sci U S A 108:2735-40|
|Gopinath, T; Mote, Kaustubh R; Veglia, Gianluigi (2011) Proton evolved local field solid-state nuclear magnetic resonance using Hadamard encoding: theory and application to membrane proteins. J Chem Phys 135:074503|
|Masterson, Larry R; Shi, Lei; Metcalfe, Emily et al. (2011) Dynamically committed, uncommitted, and quenched states encoded in protein kinase A revealed by NMR spectroscopy. Proc Natl Acad Sci U S A 108:6969-74|
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