Consequences of Mutations in Genes Encoding Cardiac Troponin C, T and I – Molecular Insights

Abstract

Cardiac troponin is the main regulatory protein of the thin filament and mediates the Ca2+sensitivity of the actin-myosin interaction. Troponin forms a heterotrimeric complex composed of the tropomyosin binding subunit (cTnT), the inhibitory subunit (cTnI) and the Ca2+-binding subunit (cTnC). A complex interplay between the cardiac troponin subunits and other thin filament proteins, as tropomyosin (Tm) and actin, is essential to regulate muscle contraction, which can be described by cross bridge cycling on the molecular level. Troponin is located on both sides of the thin filament with a stagger of about 27 Angstroms between two adjacent troponin molecules (Ebashi, 1972; Paul et al., 2009). In the thin filament each troponin binds to one tropomyosin, which covers 7 actin monomers. It is no surprise that mutations in genes encoding proteins, which participate in crossbridge cycling and its regulation, derange interactions and lead to contractile dysfunction and disease. In all three cardiac troponin subunits, changes in amino acid sequence have been identified in families with hypertrophic (HCM), restrictive (RCM) and dilated cardiomyopathy (DCM). Therefore knowledge of structure, function and interactions of the proteins is a prerequisite to understand dysfunction in disease.