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J. Biol. Chem., Vol. 279, Issue 17, 17348-17360, April 23, 2004

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Mutations of Hydrophobic Residues in the N-terminal Domain of Troponin C Affect Calcium Binding and Exchange with the Troponin C-Troponin I_96–148 Complex and Muscle Force Production^*

Jonathan P. Davis, Jack A Rall, Catalina Alionte, and Svetlana B. Tikunova

From the Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio 43210

Interactions between troponin C and troponin I play a critical role in the regulation of skeletal muscle contraction and relaxation. We individually substituted 27 hydrophobic Phe, Ile, Leu, Val, and Met residues in the regulatory domain of the fluorescent troponin C^F29W with polar Gln to examine the effects of these mutations on: (a) the calcium binding and dynamics of troponin C^F29W complexed with the regulatory fragment of troponin I (troponin I_96–148) and (b) the calcium sensitivity of force production. Troponin I_96–148 was an accurate mimic of intact troponin I for measuring the calcium dynamics of the troponin C^F29W-troponin I complexes. The calcium affinities of the troponin C^F29W-troponin I_96–148 complexes varied 243-fold, whereas the calcium association and dissociation rates varied 38- and 33-fold, respectively. Interestingly, the effect of the mutations on the calcium sensitivity of force development could be better predicted from the calcium affinities of the troponin C^F29W-troponin I_96–148 complexes than from that of the isolated troponin C^F29W mutants. Most of the mutations did not dramatically affect the affinity of calcium-saturated troponin C^F29W for troponin I_96–148. However, the Phe²⁶ to Gln and Ile⁶² to Gln mutations led to >10-fold lower affinity of calcium-saturated troponin C^F29W for troponin I_96–148, causing a drastic reduction in force recovery, even though these troponin C^F29W mutants still bound to the thin filaments. In conclusion, elucidating the determinants of calcium binding and exchange with troponin C in the presence of troponin I provides a deeper understanding of how troponin C controls signal transduction.

Received for publication, December 23, 2003 , and in revised form, February 4, 2004.

^* This work was supported in part by National Institutes of Health Grants AR20792 (to J. A. R.) and HL073600 (to S. B. T.) and by an award from the American Heart Association, Ohio Valley Affiliate (to J. P. D.). 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.

To whom correspondence should be addressed: Dept. of Physiology and Cell Biology, The Ohio State University, 209 Hamilton Hall, 1645 Neil Ave., Columbus, OH 43210. Tel.: 614-688-4467; Fax: 614-292-4888; E-mail: davis.812{at}osu.edu.

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