A dilated cardiomyopathy troponin C mutation lowers contractile force by reducing strong myosin-actin binding.

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Dweck D, Reynaldo DP, Pinto JR, Potter JD

A dilated cardiomyopathy troponin C mutation lowers contractile force by reducing strong myosin-actin binding.

J Biol Chem. 2010 Jun 4;285(23):17371-9. doi: 10.1074/jbc.M109.064105. Epub 2010 Apr 6.

PubMed ID

20371872 [ View in PubMed

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Abstract

In this study we explore the mechanisms by which a double mutation (E59D/D75Y) in cardiac troponin C (CTnC) associated with dilated cardiomyopathy reduces the Ca(2+)-activated maximal tension of cardiac muscle. Studying the single mutants (i.e. E59D or D75Y) indicates that D75Y, but not E59D, causes a reduction in the calcium affinity of CTnC in troponin complex, regulated thin filaments (RTF), and the Ca(2+) sensitivity of contraction and ATPase in cardiac muscle preparations. However, both D75Y and E59D are required to reduce the actomyosin ATPase activity and maximal force in muscle fibers, indicating that E59D enhances the effects of D75Y. Part of the reduction in force/ATPase may be due to a defect in the interactions between CTnC and cardiac troponin T, which are known to be necessary for ATPase activation. An additional mechanism for the reduction in force/ATPase comes from measurements of the binding stoichiometry of myosin subfragment-1 (S-1) to the RTF. Using wild type RTFs, 4.8 mol S-1 was bound per mol filament (seven actins), whereas with E59D/D75Y RTFs, the number of binding sites was reduced by approximately 23% to 3.7. Altogether, these results suggest that the reduction in force and ATPase activation is possibly due to a thin filament conformation that promotes fewer accessible S-1-binding sites. In the absence of any family segregation data, the functional results presented here support the concept that this is likely a dilated cardiomyopathy-causing mutation.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Calcium	Troponin C, skeletal muscle	Protein	Humans	Yes	Agonist	Details
Calcium	Troponin C, slow skeletal and cardiac muscles	Protein	Humans	Yes	Agonist	Details