Dilated and Hypertrophic Cardiomyopathy Mutations in Troponin and α-Tropomyosin Have Opposing Effects on the Calcium Affinity of Cardiac Thin Filaments

• DOI: 10.1161/circresaha.107.156380
• Publication Date: 2007-10-12T01:17:22Z
• Authors: Paul Robinson; Peter J. Griffiths; Hugh Watkins; Charles S. Redwood
• Keywords: Tropomyosin; Troponin C; Troponin T; Restrictive cardiomyopathy; Troponin complex; Dilated Cardiomyopathy

Dilated cardiomyopathy and hypertrophic (HCM) can be caused by mutations in thin filament regulatory proteins of the contractile apparatus. In vitro functional assays show that, general, presence dilated decreases Ca 2+ sensitivity contractility, whereas HCM increase it. To assess whether this phenomenon was a direct result altered affinity or troponin–tropomyosin switching, we assessed binding site cardiac troponin C wild-type mutant complex filaments using fluorescent probe (2-[4′-{iodoacetamido}aniline]-naphthalene-6-sulfonate) attached to Cys35 C. The -binding (pCa 50 =6.57±0.03) reconstituted unaffected all mutants tested, with exception I Arg145Gly mutation, which an (ΔpCa =+0.31±0.05). However, when incorporated into regulated filaments, but 1 10 α-tropomyosin affinity. Both increased =+0.41±0.02 +0.51±0.01), decreased =−0.12±0.04 −0.54±0.04), correlates our previous assays. T Asp270Asn mutant, significant decrease cooperativity. Because is major buffer cardiomyocyte sarcoplasm, suggest that changes may directly affect transient hence -sensitive disease state remodeling pathways vivo. This represents novel mechanism for class mutation.