Structures of the troponin core domain containing the cardiomyopathy-causing mutants studied by small-angle X-ray scattering

• Matsuo Tatsuhito

  Quantum Beam Science Center, Japan Atomic Energy Agency

• Takeda Soichi

  National Cerebral and Cardiovascular Center Research Institute

• Oda Toshiro

  RIKEN SPring-8 center, RIKEN Harima Institute Present address: Tokai Gakuin University

• Fujiwara Satoru

  Quantum Beam Science Center, Japan Atomic Energy Agency

抄録

Troponin (Tn), consisting of three subunits, TnC, TnI, and TnT, is a protein in the thin filaments in muscle, and, together with another thin-filament protein tropomyosin (Tm), plays a major role in regulation of muscle contraction. Various mutations of Tn cause familial hypertrophic cardiomyopathy. These mutations are directly related to aberrations in this regulatory mechanism. Here we focus on the mutations E244D and K247R of TnT, which reside in the middle of the pathway of the Ca²⁺-binding signal from TnC to Tm. These mutations induce an increase in the maximum tension of cardiac muscle without changes in Ca²⁺-sensitivity. As a first step toward elucidating the molecular mechanism underlying this functional aberration, we carried out small-angle X-ray scattering experiments on the Tn core domain containing the wild type subunits and those containing the mutant TnT in the absence and presence of Ca²⁺. Changes in the overall shape induced by the mutations were detected for the first time by the changes in the radius of gyration and the maximum dimension between the wild type and the mutants. Analysis of the scattering curves by model calculations shows that TnC adopts a dumbbell structure regardless of the mutations, and that the mutations change the distributions of the conformational ensembles so that the flexible N- and C-terminal regions of TnT become close to the center of the whole moelcule. This suggests, since these regions are related to the Tn-Tm interactions, that alteration of the Tn-Tm interactions induced by the mutations causes the functional aberration.

収録刊行物

• Biophysics and Physicobiology

  Biophysics and Physicobiology 12 (0), 145-158, 2015

  一般社団法人 日本生物物理学会

キーワード

• muscle regulatory proteins
• solution scattering
• genetic algorithm
• missense mutation

詳細情報

• CRID: 1390282680740907264
• NII論文ID: 130005118261
• DOI: 10.2142/biophysico.12.0_145
• ISSN: 21894779
• Web Site: https://www.jstage.jst.go.jp/article/biophysico/12/0/12_145/_pdf
• 本文言語コード: en
• データソース種別:
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