Familial Hypertrophic Cardiomyopathy is a common and often devastating genetic cardiac disease. Specific mutations in cardiac proteins have been identified as the root cause of this disease, but they often exert their biological effect far from the site of mutation. Such effects, usually known collectively as allostery are part of the common vocabulary of protein biochemistry, and implementation of our research program will demonstrate how such effects are also part of a multi-protein controlling component of the cardiac motor - the thin filament. In particular we focus on Ca2+ binding to cTnC (long known to be a major component in the control of a beating heart,) and phosphorylation at a known important location in cTnI. The fact that the mutations we plan to study (all in cTnT) have in some cases been shown to effect significant changes on both these control mechanisms seems to demonstrate the principle of """"""""action at a distance"""""""" but what is lacking is a translational understanding of how these changes cause disease from the molecular level to whole animal physiology. Allostery in a complex multi-component machine investigated in this fashion is thus both of great impact in basic science and of the highest significance in understanding the root cause of a devastating and relatively common human disease. To address these questions we have devised a research strategy of methodologies that range from computation on an all atom model of the troponin complex, tropomyosin, and an actin backbone, to biophysical measurements of the properties of wildtype and mutated reconstituted thin filaments, to fiber studies. The methodologies yield partially complementary yet overlapping information that provides a fully integrated analysis of this complex question. In order to better understand allostery in the function of these biological control agents in both health and disease we will study the following 2 specific aims:
Specific Aim 1 : To evaluate the molecular mechanism of the transduction of Ca2+ binding to the movement of tropomyosin and how this regulates the biophysics and physiology of the thin filament control of cardiac function in wildtype and known FHC-linked TNT1 mutations.
Specific Aim 2 : To evaluate the molecular mechanism of the phosphorylation of Ser 23/24 of cTnI in regulating myofilament activation in wildtype and known FHC-linked TNT1 mutations.

Public Health Relevance

Familial Hypertrophic Cardiomyopathy is an often devastating and common cardiac genetic disease. Specific mutations in cardiac proteins have been identified as the root cause of this disease, but they often exert their biological effect far from the site of mutation. This application is aimed at elucidating how this action at a distance causes dysfunction and eventual human disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVRS-C (02))
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Adhikari, Bishow B
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Albert Einstein College of Medicine
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United States
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Williams, Michael R; Tardiff, Jil C; Schwartz, Steven D (2018) Mechanism of Cardiac Tropomyosin Transitions on Filamentous Actin As Revealed by All-Atom Steered Molecular Dynamics Simulations. J Phys Chem Lett 9:3301-3306
Lynn, M L; Tal Grinspan, L; Holeman, T A et al. (2017) The structural basis of alpha-tropomyosin linked (Asp230Asn) familial dilated cardiomyopathy. J Mol Cell Cardiol 108:127-137
McConnell, Mark; Tal Grinspan, Lauren; Williams, Michael R et al. (2017) Clinically Divergent Mutation Effects on the Structure and Function of the Human Cardiac Tropomyosin Overlap. Biochemistry 56:3403-3413
Williams, Michael R; Lehman, Sarah J; Tardiff, Jil C et al. (2016) Atomic resolution probe for allostery in the regulatory thin filament. Proc Natl Acad Sci U S A 113:3257-62
Tardiff, Jil C (2016) The Role of Calcium/Calmodulin-Dependent Protein Kinase II Activation in Hypertrophic Cardiomyopathy. Circulation 134:1749-1751
Tardiff, Jil C; Carrier, Lucie; Bers, Donald M et al. (2015) Targets for therapy in sarcomeric cardiomyopathies. Cardiovasc Res 105:457-70
Duncker, Dirk J; Bakkers, Jeroen; Brundel, Bianca J et al. (2015) Animal and in silico models for the study of sarcomeric cardiomyopathies. Cardiovasc Res 105:439-48
Moore, Rachel K; Abdullah, Salwa; Tardiff, Jil C (2014) Allosteric effects of cardiac troponin TNT1 mutations on actomyosin binding: a novel pathogenic mechanism for hypertrophic cardiomyopathy. Arch Biochem Biophys 552-553:21-8
Moore, Rachel K; Grinspan, Lauren Tal; Jimenez, Jesus et al. (2013) HCM-linked ?160E cardiac troponin T mutation causes unique progressive structural and molecular ventricular remodeling in transgenic mice. J Mol Cell Cardiol 58:188-98
Tardiff, Jil C (2012) It's never too early to look: subclinical disease in sarcomeric dilated cardiomyopathy. Circ Cardiovasc Genet 5:483-6

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