Disease-causing mutations in cardiac troponin T: Identification of a critical tropomyosin-binding region

ABSTRACT Fifteen percent of the mutations causing familial hypertrophic cardiomyopathy are in the troponin T gene. Most mutations are clustered between residues 79 and 179, a region known to bind to tropomyosin at the C-terminus near the complex between the N- and C-termini. Nine mutations were introduced into a troponin T fragment, Gly-hcTnT70-171, that is soluble, alpha-helical, binds to tropomyosin, promotes the binding of tropomyosin to actin, and stabilizes an overlap complex of N-terminal and C-terminal tropomyosin peptides. Mutations between residues 92 and 110 (Arg92Leu, Arg92GIn, Arg92Trp, Arg94Leu, Ala104Val, and Phel110lle) impair tropomyosin-dependent functions of troponin T. …