Defective Dynamic Properties of Human Cardiac Troponin Mutations

Abstract

Mutations in Troponin I (TnI) and Troponin T (TnT) are closely linked to familial hypertrophic cardiomyopathy (FHC) and hypertrophic cardiomyopathy (HCM), but the underlying molecular mechanism is not yet well understood. There might be a close link between the defective dynamic properties and the functional aberrations of hcTroponin. To prove this hypothesis, we undertook detailed NMR relaxation measurements of [(2)H, (13)C, (15)N] labeled proteins reconstituted into hcTroponin in both the Ca(2+)- and the Mg(2+)-loaded state. The wild-type TnI and two FHC causing mutations, TnI(G203S) and TnI(DeltaK183), were investigated. To ensure that defective dynamic properties are not only a particular feature for mutations in the flexible part of TnI, measurements of the TnT mutation TnT(R278P) were also performed. For all mutations significant dynamic changes in the area for Troponin C (TnC) and actin-Tm binding were obtained. These measurements provide important information to understand the functional aberrations of FHC and HCM causing mutation in human cardiac Troponin (hcTn).