TMEM16Aカルシウム活性化塩化物チャネルの冷凍-EM構造
Shangyu Dang1, Shengjie Feng2, Jason Tien2
1Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA.
Nature
|December 14, 2017
まとめ
この研究では,TMEM16Aのカルシウム活性化塩化チャネル (CaCC) の新しい原子構造が示され,そのイオン浸透孔と機能的状態が明らかになりました. これらの発見は,アニオン伝導とチャネルゲートを制御する重要な残留物を特定し,CaCCの生理学的役割を理解するために重要である.
科学分野:
- 構造生物学
- 分子生理学
- イオンチャネル機能
背景:
- TMEM16Aによってコードされるカルシウム活性化塩化物チャネル (CaCC) は,神経信号伝達と滑らかな筋肉の収縮を含む多くの生理学的プロセスに不可欠です.
- TMEM16Aの構造を理解することは,アニオン浸透の仕組みと様々な生物学的機能における役割を解明するために不可欠です.
- これまでのCaCCに関する構造的洞察は,同質モデリングと低解像度技術に依存して限られていた.
研究 の 目的:
- マウスTMEM16Aのトランスメブランドメインの de novo原子構造を決定する.
- チャンネルゲートとアニオン選択性にとって重要なイオン浸透孔と残留物を特定する.
- CaCCアニオン伝導の構造的基礎とその異なる機能的状態を解明する.
主な方法:
- 単粒子の電子冷凍顕微鏡 (cryo-EM) を用いて,ナノディスクとローリルマルトース・ネオペンチルグリコールにおけるTMEM16Aの原子構造を決定した.
- 構造的な発見を検証するために,変異性および電気生理学的研究が行われました.
- 異なる機能的状態を捉えるために,異なる環境 (ナノディスク,洗剤) の構造を分析する.
主要な成果:
- TMEM16Aトランスメブランドメインの2つの異なる原子構造が解明され,イオン浸透孔が明らかになった.
- 構造は異なる機能的状態を捉え,解消されたCa2+イオンと狭い孔を持つ可能性が高い閉じた状態を含みます.
- ミュタゲネシスと電気生理学では,アニオン相互作用と選択性に影響を与える10の孔内膜残留物と,チャネルゲートを調節する7の残留物が見つかりました.
結論:
- この研究は,TMEM16Aの高解像度構造を提供し,イオン浸透経路の構造を明確にします.
- アニオン伝導,選択性,ゲーティングに関与する主要な残留物は識別され,機械的洞察を提供している.
- これらの発見は,TMEM16Aが様々な生理学的プロセスでどのように機能するかについての理解を深めています.
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