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Functional aberration of myofibrils by cardiomyopathy-causing mutations in the coiled-coil region of the troponin-core domain |
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| Authors: | Fumiko Matsumoto Toshiyuki Chatake Satoru Fujiwara |
| Institution: | a Quantum Beam Science Directorate, Japan Atomic Energy Agency, 2-4 Shirakata-Shirane, Tokai-mura, Naka-gun, Ibaraki 319-1195, Japan b ERATO Project ‘Actin Filament Dynamics’, Japan Science and Technology Agency, Sayo, Hyogo 679-5148, Japan c Kyoto University Research Reactor Institute, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan d Structural Biology Research Center and Division of Biological Science, Graduate School of Science, Nagoya University, Furo-cho, Nagoya 464-8602, Japan |
| Abstract: | Two cardiomyopathy-causing mutations, E244D and K247R, in human cardiac troponin T (TnT) are located in the coiled-coil region of the Tn-core domain. To elucidate effects of mutations in this region on the regulatory function of Tn, we measured Ca2+-dependent ATPase activity of myofibrils containing various mutants of TnT at these residues. The results confirmed that the mutant E244D increases the maximum ATPase activity without changing the Ca2+-sensitivity. The mutant K247R was shown for the first time to have the effect similar to the mutant E244D. Furthermore, various TnT mutants (E244D, E244M, E244A, E244K, K247R, K247E, and K247A) showed various effects on the maximum ATPase activity while the Ca2+-sensitivity was unchanged. Molecular dynamics simulations of the Tn-core containing these TnT mutants suggested that the hydrogen-bond network formed by the side chains of neighboring residues around residues 244 and 247 is important for Tn to function properly. |
| Keywords: | Troponin Cardiomyopathy Muscle regulation ATPase activity Hydrogen bond Molecular dynamics |
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