What is it about?
The contraction of skeletal and cardiac muscles is controlled by calcium via conformational changes of the myofilament regulatory proteins troponin and tropomyosin. Physiological and medical research over the past four decades was based on a molecular model in which troponin interacts with tropomyosin via its subunit TnT at two binding sites. Our present study identified a third tropomyosin-binding site in the highly conserved C-terminal end segment of TnT. This site also binds F-actin-Tm filament and F-actin alone and functions as a conformationally modulated inhibitory regulator. In addition to revising our understanding of the dynamic interactions in the thin filament regulation of muscle contraction with physiological and medical importance, the functionality of this novel site is retained in the form of isolated free peptide to modulate cardiac muscle contractile kinetics as a potential therapeutic reagent.
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Why is it important?
Physiological and medical research of myofilament regulation was based on the 40 years old model that troponin interacts with tropomyosin via its subunit TnT at two binding sites. The identification and characterization of the third tropomyosin site revises the molecular model of calcium regulation of skeletal and cardiac muscle contraction and relaxation, laying a new foundation to better understand muscle physiology and pathological conditions and promote therapeutic developments.
Perspectives
Protein structure-function relationship is at the leading edge of biomedical research in the post-genome era. Demonstrating the combined power of current knowledge and research approaches from molecular evolution to genetic engineering to protein biochemistry and biophysical analysis to physiological functions and human disease models, our investigations to identify and characterize the novel third tropomyosin-binding site of TnT revises the model of myofilament regulation of skeletal and cardiac muscle contractility with new insights into the structure-function relationship of troponin in altering the kinetics of muscle contraction in physiological adaptation and diseases.
J.-P. Jin
University of Illinois at Chicago
Read the Original
This page is a summary of: The highly conserved C-terminal end segment of troponin T binds tropomyosin and actin to function in modulating contractile kinetics, Proceedings of the National Academy of Sciences, July 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2507107122.
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