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- W4319937650 abstract "The troponin complex plays a central role in the Ca2+-regulation of striated muscle contraction and relaxation. Its inhibitory subunit TnI and tropomyosin (Tm)-binding subunit TnT are striated muscle-specific proteins evolved from a TnI-like ancestor gene. Deletion of the evolutionarily added N-terminal variable region of cardiac TnT (cTnT-ND) by restrictive proteolysis in response to myocardial energetic crisis and failure reduces ventricular peak contractile velocity to increase ejection time and increase stroke volume (J Physiol 586:3537-50, 2008). This compensatory effect corresponds to the restoration of an epitope structure recognized by a monoclonal antibody raised against the C-terminal end 27 amino acids (AA) Tm-binding segment of TnI (TnI-C27, JMCC 136:42-52, 2019). To reveal the underlying mechanism of this function of cTnT-ND, we located the conditional TnI-C27-like structure in the 14 AA C-terminal end segment of cTnT (cTnT-C14). Microplate protein binding studies and localized surface plasmon resonance analysis demonstrated that the highly conserved cTnT-C14 segment is a novel Tm-binding site besides the known Tm-binding sites 1 and 2. Quantitative data show that this cTnT-ND-enhanced third Tm-binding site of TnT functions in determining the kinetics of cardiac muscle. The molecular conformation and Tm-binding of mammalian cTnT-C14 peptide are directly regulated by physiological levels of Ca2+ with higher affinity at pCa 9 than that at pCa 4. Deletion of the last 2 AA in cTnT-C14 largely abolished Tm-binding. Cardiomyopathy mutation R286C significantly increases cTnT-C14's binding affinity for Tm at pCa 9 whereas mutation R278C increases Tm-binding with diminished Ca2+ regulation. These findings provide novel insights into the regulation of striated muscle contraction and relaxation with physiological and pathophysiological significances and identify a myofilament mechanism to improve cardiac function and treat heart failure." @default.
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- W4319937650 date "2023-02-01" @default.
- W4319937650 modified "2023-10-16" @default.
- W4319937650 title "The C-terminal end segment of troponin T is a novel tropomyosin-binding site directly regulated by Ca2+ to determine the kinetics of cardiac muscle" @default.
- W4319937650 doi "https://doi.org/10.1016/j.bpj.2022.11.822" @default.
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