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ヒト脂質エクスポーターABCA1の構造

Hongwu Qian¹, Xin Zhao¹, Pingping Cao¹

¹State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China; Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.

|June 13, 2017

まとめ

ABCA1の冷凍EM構造は,高密度脂質 (HDL) の生成に不可欠なコレステロールとリンパ脂質の輸送におけるその役割を明らかにする. この発見は,脂質の輸出メカニズムと関連する病気を理解するのに役立ちます.

科学分野:

生物化学
構造生物学
分子医学

背景:

ATP結合カセット (ABC) トランスポーター ABCA1は,新生高密度脂質タンパク質 (HDL) の形成に不可欠なアポリポプロテインA- I (apoA- I) への細胞脂質流出を促進します.
ABCA1機能障害は,タンジェ病と家族性HDL欠乏症に関連しており,その臨床的重要性を強調しています.

研究の目的:

人間のABCA1の高解像度冷凍電子顕微鏡 (cryo-EM) 構造を決定する.
ABCA1媒介の脂質輸送の構造的基礎とその疾患を引き起こす変異との関係を解明する.

主な方法:

ヒトのABCA1の構造を解明するために,冷凍電子顕微鏡 (cryo-EM) を用いた.
病原性メカニズムを理解するために,疾患に関連する変異のマッピングを含む構造分析.

主要な成果:

人間のABCA1の冷凍-EM構造は,全体として4. 1 Å,細胞外領域では3. 9 Åの解像度で決定された.
構造は,核酸無核酸結合ドメイン (NBDs),トランスメブランドメイン (TMDs) の間の狭い細胞内インターフェース,および細胞外ドメイン内の長方形の水害性トンネルを明らかにした.
構造マッピングは多くの病気に関連する変異のメカニズムに洞察を与えました

結論:

決定された構造は,脂質流出におけるABCA1機能の分子理解を提供します.
ABCA1を媒介する脂質輸出のための潜在的な"側面アクセス"メカニズムが提案されており,従来のモデルとは異なる.
この構造的な洞察は,HDL代謝および関連する障害を理解するために不可欠です.

キーワード:

ABCトランスポーター ABCA1 についてタンジャー病クリオ・エム構造家族性HDL欠乏症脂質の輸出者新生HDL形成コレステロールの逆輸送

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