TMEM16Fによるカルシウム依存性フォスフォリピドスクラミング
Jun Suzuki1, Masato Umeda, Peter J Sims
1Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.
Nature
|November 26, 2010
まとめ
トランスメブランタンパク質16F (TMEM16F) は,カルシウム依存性フォスファティディルセリン (PtdSer) の細胞表面への曝露に不可欠です. TMEM16Fの変異は,欠陥のあるリンパ脂質の乱交に関連した障害であるスコット症候群を引き起こす.
科学分野:
- 細胞生物学 細胞生物学
- バイオケミストリー バイオケミストリー
- 膜生物物理学 膜生物物理学
背景:
- フォスフォリピドは動物細胞のプラズマ膜に非対称的に分布しています.
- フォスファティディルセリン (PtdSer) が活性化された血小板に曝されるような,フォスフォリピド不対称性の障害は,血液の凝固などの生物学的プロセスを引き起こす.
- スクランブレーゼによって媒介されるCa(2+) 依存のリン酸脂質の乱交の分子機構は,ほとんど不明のままである.
研究 の 目的:
- Ca(2+) 依存性フォスファティディルセリン (PtdSer) 曝露に起因する分子成分を特定する.
- 細胞システムにおけるフォスフォリピドの乱れの原因となるメカニズムを解明する.
主な方法:
- マウスのB細胞系 (Ba/F3) を用いて表現クローニングを行い,PtdSerの曝露を高めるために設計された.
- TMEM16F.のサイト・ディレクテッド・ミュータジェネシスと機能分析.
- TMEM16F遺伝子変異を携えているスコット症候群の患者の分析.
主要な成果:
- TMEM16Fは,Ca(2+) に依存するPtdSer曝露の重要な成分として特定されました.
- TMEM16Fの構成的に活性な変異体が,自発的なPtdSer被曝を誘導した.
- ワイルド型TMEM16Fは,血に局所化され,Ca2+) に依存したフォスフォリピドスクランブルを媒介する.
- スコット症候群の患者はTMEM16F変異を呈し,早すぎるタンパク質の解消につながった.
結論:
- TMEM16Fは,フォスフォリピド非対称性とPtdSer曝露の調節に重要な役割を果たしています.
- TMEM16Fは,Ca(2+) に依存したフォスフォリピドスクランブラゼとして機能する.
- TMEM16Fの欠陥は,スコット症候群に直接関係しており,臨床的関連性を強調しています.
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