人間のナトリウム漏れ経路の構造 NALCN

Marc Kschonsak¹, Han Chow Chua², Cameron L Noland¹

¹Department of Structural Biology, Genentech Inc., San Francisco, CA, USA.

Nature

|July 23, 2020

まとめ

FAM155Aを用いて,神経刺激性にとって重要なNALCNチャネルの構造を決定した. これは,どのように突然変異が神経疾患を引き起こすかを明らかにし,NALCNチャネル病変の標的を提供している.

科学分野:

神経科学
分子生物学
構造生物学

背景:

ナトリウム (Na+) の漏れ電流は神経の電気的興奮に不可欠です.
非選択的電圧ゲートナトリウムチャネル (NALCN) は,ニューロンの主要な背景Na+チャネルである.
NALCNは重要な生理学的機能を調節し,その機能不全は重度の神経疾患につながる.

研究の目的:

補助サブユニットであるFAM155Aと複合したNALCNチャネルの構造を明らかにする.
NALCNゲート,イオン選択性,および薬理学の基礎となる分子機構を理解する.
NALCNチャネル病変の構造的基礎を提供すること.

主な方法:

NALCN-FAM155A複合体の構造を決定するための冷凍電子顕微鏡 (Cryo-EM)
イオン選択性フィルター,孔,および電圧センサー領域を含む重要な機能領域を特定するための構造分析.
患者の変異部位と,その構造を分析する.

主要な成果:

NALCNとFAM155Aの複合体の構造が決定され,FAM155Aが選択性フィルターをシールドする役割を明らかにした.
NALCNの中央腔は,横の毛穴が閉ざされ,その薬理学に影響を与えています.
非対称な電圧センサードメインは新しい調節メカニズムを示唆し患者の変異は閉じた毛穴の門の周りに集まります

結論:

この研究は,NALCNチャンネルとFAM155Aとの相互作用に関する最初の構造的洞察を提供します.
NALCNの構造を理解することは,その生理学を調査し,NALCNチャネル病変の治療法を開発するための枠組みを提供します.
この発見は,NALCNに関連する神経疾患における機能獲得変異の構造的基礎を強調しています.

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