TitleMolecular mechanisms and structural features of cardiomyopathy-causing troponin T mutants in the tropomyosin overlap region.
Publication TypeJournal Article
Year of Publication2017
AuthorsGangadharan B, Sunitha MS, Mukherjee S, Chowdhury RRoy, Haque F, Sekar N, Sowdhamini R, Spudich JA, Mercer JA
JournalProc Natl Acad Sci U S A
Date Published2017 10 17

Point mutations in genes encoding sarcomeric proteins are the leading cause of inherited primary cardiomyopathies. Among them are mutations in the gene that encodes cardiac troponin T (TnT). These mutations are clustered in the tropomyosin (Tm) binding region of TnT, TNT1 (residues 80-180). To understand the mechanistic changes caused by pathogenic mutations in the TNT1 region, six hypertrophic cardiomyopathy (HCM) and two dilated cardiomyopathy (DCM) mutants were studied by biochemical approaches. Binding assays in the absence and presence of actin revealed changes in the affinity of some, but not all, TnT mutants for Tm relative to WT TnT. HCM mutants were hypersensitive and DCM mutants were hyposensitive to Ca in regulated actomyosin ATPase activities. To gain better insight into the disease mechanism, we modeled the structure of TNT1 and its interactions with Tm. The stability predictions made by the model correlated well with the affinity changes observed in vitro of TnT mutants for Tm. The changes in Ca sensitivity showed a strong correlation with the changes in binding affinity. We suggest the primary reason by which these mutations between residues 92 and 144 cause cardiomyopathy is by changing the affinity of TnT for Tm within the TNT1 region.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID28973951
PubMed Central IDPMC5651771
Grant ListR01 GM033289 / GM / NIGMS NIH HHS / United States
R01 HL117138 / HL / NHLBI NIH HHS / United States