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Structural basis for catalysis and substrate specificity of human ACAT1

机译：人体ACAT1的催化和底物特异性的结构基础

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摘要

The structure of human ACAT1, which catalyses the transfer of an acyl group from acyl-coenzyme A to cholesterol to form cholesteryl ester, is resolved by cryo-electron microscopy.As members of the membrane-bound O-acyltransferase (MBOAT) enzyme family, acyl-coenzyme A:cholesterol acyltransferases (ACATs) catalyse the transfer of an acyl group from acyl-coenzyme A to cholesterol to generate cholesteryl ester, the primary form in which cholesterol is stored in cells and transported in plasma(1). ACATs have gained attention as potential drug targets for the treatment of diseases such as atherosclerosis, Alzheimer's disease and cancer(2-7). Here we present the cryo-electron microscopy structure of human ACAT1 as a dimer of dimers. Each protomer consists of nine transmembrane segments, which enclose a cytosolic tunnel and a transmembrane tunnel that converge at the predicted catalytic site. Evidence from structure-guided mutational analyses suggests that acyl-coenzyme A enters the active site through the cytosolic tunnel, whereas cholesterol may enter from the side through the transmembrane tunnel. This structural and biochemical characterization helps to rationalize the preference of ACAT1 for unsaturated acyl chains, and provides insight into the catalytic mechanism of enzymes within the MBOAT family(8).
机译：催化从酰基 - 辅酶A转移到胆固醇中以形成胆固醇酯的人ACAT1的结构通过冷冻电子显微镜分辨。膜结合的O-酰基转移酶（MBoat）酶系列的成员，酰基 - 辅酶A：胆固醇酰基转移酶（Acats）催化酰基将酰基转移到酰基 - 辅酶A中以产生胆固醇，以产生胆固醇酯，其中胆固醇储存在细胞中并在血浆（1）中运输的主要形式。 Acats患有潜在的药物靶向治疗疾病，如动脉粥样硬化，阿尔茨海默病和癌症（2-7）。在这里，我们将Lugo-Croto-Croto-Electron显微镜结构呈现为二聚体二聚体的二聚体。每个重选聚物由九个跨膜段组成，其包围细胞溶质隧道和跨膜隧道，该隧道在预测的催化遗址上会聚。来自结构引导的突变分析的证据表明，酰基 - 辅酶A通过细胞溶质隧道进入活性位点，而胆固醇可以通过跨膜隧道从侧面进入。这种结构和生化表征有助于将ACAT1的偏好合理化为不饱和酰基链，并提供对Mboat家族内酶催化机制（8）的倾向。

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  • 来源
    《Nature》 |2020年第7808期|333-338|共6页
  • 作者

    Qian Hongwu; Zhao Xin; Yan Renhong; Yao Xia; Gao Shuai; Sun Xue; Du Ximing; Yang Hongyuan; Wong Catherine C. L.; Yan Nieng;

  • 作者单位

    Princeton Univ Dept Mol Biol Princeton NJ 08544 USA;

    Tsinghua Univ Tsinghua Peking Joint Ctr Life Sci Beijing Adv Innovat Ctr Struct Biol Sch Life Sci State Key Lab Membrane Biol Beijing Peoples R China;

    Westlake Univ Sch Life Sci Key Lab Struct Biol Zhejiang Prov Hangzhou Peoples R China|Westlake Inst Adv Study Inst Biol Hangzhou Peoples R China;

    Princeton Univ Dept Mol Biol Princeton NJ 08544 USA;

    Princeton Univ Dept Mol Biol Princeton NJ 08544 USA;

    Peking Univ Peking Tsinghua Ctr Life Sci State Key Lab Nat & Biomimet Drugs Ctr Precis Med Multiom Res Sch Pharmaceut Sci Beijing Peoples R China;

    Univ New South Wales Sch Biotechnol & Biomol Sci Sydney NSW Australia;

    Univ New South Wales Sch Biotechnol & Biomol Sci Sydney NSW Australia;

    Peking Univ Peking Tsinghua Ctr Life Sci State Key Lab Nat & Biomimet Drugs Ctr Precis Med Multiom Res Sch Pharmaceut Sci Beijing Peoples R China;

    Princeton Univ Dept Mol Biol Princeton NJ 08544 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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