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TNNT2 mutations in the tropomyosin binding region of TNT1 disrupt its role in contractile inhibition and stimulate cardiac dysfunction

Year: 2020
Type: article
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.
DOI: 10.1073/pnas.2001692117
Authors: Aditi Madan, Meera C. Viswanathan, Kathleen C. Woulfe, William Schmidt, Agnes Sidor, Ting Liu, Tran H. Nguyen, Bosco Trinh, Cortney Wilson, Sineej Madathil, Georg Vogler, Brian O’Rourke, Brandon J. Biesiadecki, Larry S. Tobacman, Anthony Cammarato
Institutions: Johns Hopkins University, University of Colorado Anschutz, University of Colorado Denver, Sanford Burnham Prebys Medical Discovery Institute, University of Illinois Chicago, The Ohio State University
Language: English
Field: Medicine
Open Access status: green
Awards: G186511478, G3294718052, G3355343782, Molecular Determinants of Mitochondrial Instability and Arrhythmias, G4931865217, G5866671933, G6310176720, G9000098025, PATHOGENESIS AND IN VIVO SUPPRESSION OF THIN FILAMENT-BASED CARDIOMYOPATHIES
OpenAlex ID: W3043980858
FWCI: 2.79
Cites: 78
Cited by: 29
Related to: 10