Evolution, Regulation, and Function of N-terminal Variable Region of Troponin T: Modulation of Muscle Contractility and Beyond

Abstract

Troponin T (TnT) is the tropomyosin-binding and thin filament-anchoring subunit of the troponin complex in skeletal and cardiac muscles. At the center of the sarcomeric thin filament regulatory system of striated muscles, TnT plays an essential role in transducing Ca(2+) signals in the regulation of contraction. Having emerged predating the history of vertebrates, TnT has gone through more than 500 million years of evolution that resulted in three muscle-type-specific isoforms and numerous alternative RNA splicing variants. The N-terminal region of TnT is a hypervariable structure responsible for the differences among the TnT isoforms and splice forms. This focused review summarizes our current knowledge of the molecular evolution of the N-terminal variable region and its role in the structure and function of TnT. In addition to the physiologic and pathophysiologic significances in modifying the contractility of skeletal and cardiac muscles during development and in adaptation to stress and disease conditions, the hyperplasticity of the N-terminal region of TnT demonstrates an informative example for the evolution of protein three-dimensional structure and provides insights into the molecular evolution and functional potential of proteins.

Keywords: N-terminal variable region; alternative splicing; calcium regulation of contraction; molecular evolution; protein conformation; proteolytic modification; striated muscle thin filament; troponin T isoforms.