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J. Biol. Chem., Vol. 281, Issue 19, 13471-13477, May 12, 2006

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Increased Ca²⁺ Affinity of Cardiac Thin Filaments Reconstituted with Cardiomyopathy-related Mutant Cardiac Troponin I^*

From the Department of Physiology and Biophysics and Center for Cardiovascular Research, College of Medicine, University of Illinois, Chicago, Illinois 60612

To understand the molecular mechanisms whereby cardiomyopathy-related cardiac troponin I (cTnI) mutations affect myofilament activity, we have investigated the Ca²⁺ binding properties of various assemblies of the regulatory components that contain one of the cardiomyopahty-related mutant cTnI. Acto-S1 ATPase activities in reconstituted systems were also determined. We investigated R145G and R145W mutations from the inhibitory region and D190H and R192H mutations from the second actin-tropomyosin-binding site. Each of the four mutations sensitized the acto-S1 ATPase to Ca²⁺. Whereas the mutations from the inhibitory region increased the basal level of ATPase activity, those from the second actin-tropomyosin-binding site did not. The effects on the Ca²⁺ binding properties of the troponin ternary complex and the troponin-tropomyosin complex with one of four mutations were either desensitization or no effect compared with those with wild-type cTnI. All of the mutations, however, affected the Ca²⁺ sensitivities of the reconstituted thin filaments in the same direction as the acto-S1 ATPase activity. Also the thin filaments with one of the mutant cTnIs bound Ca²⁺ with less cooperativity compared with those with wild-type cTnI. These data indicate that the mutations found in the inhibitory region and those from the second actin-tropomyosin site shift the equilibrium of the states of the thin filaments differently. Moreover, the increased Ca²⁺ bound to myofilaments containing the mutant cTnIs may be an important factor in triggered arrhythmias associated with the cardiomyopathy.

Received for publication, August 30, 2005 , and in revised form, March 7, 2006.

^* This work was supported by American Heart Association Scientist Development Grant 0230038N (to T. K.) and National Institutes of Health Grants R37 HL 22231 and P01 HL 62426 (to R. J. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Physiology and Biophysics, University of Illinois, 835 S. Wolcott Ave. (M/C 901), Chicago, IL 60612. Tel.: 312-996-7151; Fax: 312-996-1414; E-mail: tkoba{at}uic.edu.

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