Functional consequences of a carboxyl terminal missense mutation Arg278Cysin human cardiac troponin T

A carboxyl terminal missense mutant Arg278Cys of human cardiac troponin T t hat causes familial hypertrophic cardiomyopathy was expressed in Escherichi a coli purified, and exchanged into rabbit cardiac skinned muscle fibers us ing a troponin exchange technique. Compared to the fibers exchanged with hu man cardiac wild-type troponin T, the fibers exchanged with the mutant Arg2 78Cys developed less maximum force with a decreased cooperativity and a sli ghtly increased Ca2+ sensitivity, resulting in a significant elevation of s ub-half-maximal force, Since intact cardiac muscle is thought to never be a ctivated beyond the half-maximum level, the results suggest that an enhance d myofilament response to Ca2+ may be responsible for the pathogenesis of h ypertrophic cardiomyopathy associated with this mutation. The results also provide the first evidence that the carboxyl terminal region of cardiac tro ponin T plays an important role probably through its interaction with tropo myosin in allowing troponin complex to inhibit the muscle contraction at lo w Ca2+, in agreement with the hypothesis deduced from the previous studies on fast skeletal troponin T. (C) 1999 Academic Press.