Mechanistic understanding of the "flip-flop switch" hypothesis generated by phospholipid translocases

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K19259
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 44:Biology at cellular to organismal levels, and related fields
• Research Institution: University of Shizuoka
• Principal Investigator: Hara Yuji 静岡県立大学, 薬学部, 教授 (60362456)
• Co-Investigator(Kenkyū-buntansha): 永森 收志 東京慈恵会医科大学, 医学部, 准教授 (90467572)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Keywords: リン脂質 / フリップ・フロップスイッチ / イオンチャネル制御

Outline of Final Research Achievements

Phospholipids, the main components of the plasma membrane, are known to be asymmetrically distributed to the inner and outer leaflets. This phenomenon is generated by the activity of phospholipid translocases, and is involved in a variety of cellular processes including cell survival, cell migration and so on. We have hypothesized that the transbilayer movements of phospholipids called "flip-flop switch" regulates the functions of membrane proteins. In this study, we performed a series of experiments to address our hypothesis, and identified a TRP channel protein as a candidate to be regulated by flip-flop switch. Additional experiments such as proteome analysis and generation of mutant mouse models helped us to further elucidate the molecular mechanisms.

Free Research Field

薬系衛生および生物化学関連

Academic Significance and Societal Importance of the Research Achievements

これまで非常に多くの研究者が脂質と膜タンパク質の相互作用について従事してきた。しかし脂質は水に溶けない物性、またゲノムに直接コードされない理由から、科学技術が進歩した現在でも解析し難い対象であり、脂質環境の微細なゆらぎと膜タンパク質の機能連関の解明は未だ困難である。本研究の中心課題「リン脂質フリップ・フロップ スイッチにより制御される膜タンパク質群の網羅的同定」を通じ、膜脂質とタンパク質の織りなす多様な相互作用を理解し、生体膜に機能的な多様性を賦与する分子機構の解明につながる。さらに膜タンパク質が関わる細胞応答、個体レベルの恒常性維持機構、病態発症機構等の理解深化が期待される。