Key result
In vitro and in silico analysis of TNT1 mutants revealed a striking correlation between binding affinities for tropomyosin and changes in calcium sensitivity of regulated actomyosin ATPase activities.
Changes in the affinity of Troponin T for tropomyosin due to mutations in residues 92-144 are likely the primary cause of cardiomyopathy for mutations in this region.
No immediate implications for cardiomyopathy care; leaves open whether tropomyosin affinity drives human disease.
Significance Mutations in genes encoding sarcomeric proteins are the major cause of primary inherited cardiomyopathies. Troponin T (TnT), encoded by TNNT2 , harbors most of its pathogenic mutants at TNT1 (residues ∼80–180 of TnT). TNT1 is known to interact with tropomyosin (Tm). In this study, we have analyzed TNT1 mutants using in vitro and in silico methods and correlated the results. We also found a striking correlation between binding affinities for Tm and changes in the calcium sensitivity of regulated actomyosin ATPase activities within residues 92–144. These data are consistent with reducing or increasing the affinity of TnT for Tm as the primary cause of cardiomyopathy for mutations in this region, suggesting a smaller Tm binding region.
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Gangadharan et al. (2017) studied Primary inherited cardiomyopathies. TNT1 mutants was evaluated on Binding affinities for Tm and changes in calcium sensitivity of regulated actomyosin ATPase activities. In vitro and in silico analysis of TNT1 mutants revealed a striking correlation between binding affinities for tropomyosin and changes in calcium sensitivity of regulated actomyosin ATPase activities.
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