Analysis of a novel ryanodine receptor modulation mechanism using physiological experiments and molecular dynamics calculations

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07306
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48020:Physiology-related
• Research Institution: Jikei University School of Medicine
• Principal Investigator: Yamazawa Toshio 東京慈恵会医科大学, 医学部, 教授 (00282616)
• Co-Investigator(Kenkyū-buntansha): 村山 尚 順天堂大学, 医学部, 先任准教授 (10230012) ; 小川 治夫 京都大学, 薬学研究科, 准教授 (40292726)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: リアノジン受容体 / Ca2+放出 / 悪性高熱症

Outline of Final Research Achievements

Type 1 ryanodine receptor (RyR1) on the sarcoplasmic reticulum membrane is a giant ion channel that exhibits Ca2+-induced Ca2+ release (CICR) properties. However, the mechanism by which a single amino acid substitution alters giant ion channel activity and causes disease is unknown. We performed molecular dynamics (MD) calculations to understand the dynamic structure from the viewpoint of information thermodynamics and proposed that nine different salt/hydrogen bond residue pairs between subdomains are involved in the stability of the domain structure. This hypothesis was supported by functional analysis of disease mutants of RyR1 in physiological experiments.

Free Research Field

生理学

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、MD計算と生理実験を組み合わせて、RyR1のN末領域内サブドメインの境界でのチャネル機能異常を伴う変異RyR1の構造変化を示した。このようなアプローチは、１アミノ酸残基置換が蛋白全体の構造・機能を変調させる仕組みを理解するためのモデルケースになり得るものと考えられる。また、塩橋/水素結合と点変異のRyR1チャネル機能に関するデータは、変異による病態予測を高精度で行うことが可能となり、患者負担の軽減による社会的な利益も大きいことが期待される。