Functional consequences of a carboxyl terminal missense mutation Arg278Cys in human cardiac troponin T. |
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Authors: | S Morimoto H Nakaura F Yanaga I Ohtsuki |
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Institution: | Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. |
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Abstract: | A carboxyl terminal missense mutant Arg278Cys of human cardiac troponin T that causes familial hypertrophic cardiomyopathy was expressed in Escherichia coli, purified, and exchanged into rabbit cardiac skinned muscle fibers using a troponin exchange technique. Compared to the fibers exchanged with human cardiac wild-type troponin T, the fibers exchanged with the mutant Arg278Cys developed less maximum force with a decreased cooperativity and a slightly increased Ca(2+) sensitivity, resulting in a significant elevation of sub-half-maximal force. Since intact cardiac muscle is thought to never be activated beyond the half-maximum level, the results suggest that an enhanced myofilament response to Ca(2+) may be responsible for the pathogenesis of hypertrophic cardiomyopathy associated with this mutation. The results also provide the first evidence that the carboxyl terminal region of cardiac troponin T plays an important role probably through its interaction with tropomyosin in allowing troponin complex to inhibit the muscle contraction at low Ca(2+), in agreement with the hypothesis deduced from the previous studies on fast skeletal troponin T. |
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