<i>TNNT2</i> mutations in the tropomyosin binding region of TNT1 disrupt its role in contractile inhibition and stimulate cardiac dysfunction
Aditi Madan, Meera Viswanathan, Kathleen C. Woulfe, William M. Schmidt, Agnes Sidor, Ting Liu, Tran H. Nguyen, Bosco Trinh, Cortney E. Wilson, Sineej Madathil, Georg Vogler, Brian O’Rourke, Brandon J. Biesiadecki, Larry S. Tobacman, Anthony Cammarato
Abstract
cardiac performance, rat myofibrillar and cardiomyocyte properties, and human TNT1's propensity to inhibit myosin-driven, F-actin-tropomyosin motility were evaluated. Our data collectively demonstrate that removing conserved, charged residues in TNT1's tropomyosin-binding domain impairs TnT's contribution to inhibitory tropomyosin positioning and relaxation. Thus, TNT1 may modulate acto-myosin activity by optimizing F-actin-tropomyosin interfacial contacts and by binding to actin, which restrict tropomyosin's movement to activating configurations. HCM/RCM mutations, therefore, highlight TNT1's essential role in contractile regulation by diminishing its tropomyosin-anchoring effects, potentially serving as the initial trigger of pathology in our animal models and humans.