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Structure of the Human ACP-ISD11 Heterodimer

机译：人ACP-ISD11异二聚体的结构

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摘要

In recent years, the mammalian mitochondrial protein complex for iron-sulfur cluster assembly has been the focus of important studies. This is partly because of its high degree of relevance in cell metabolism and because mutations of the involved proteins are the cause of several human diseases. Cysteine desulfurase NFS1 is the key enzyme of the complex. At present, it is well-known that the active form of NFS1 is stabilized by the small protein ISD11. In this work, the structure of the human mitochondrial ACP-ISD11 heterodimer was determined at 2.0 A resolution. ACP-ISD11 forms a cooperative unit stabilized by several ionic interactions, hydrogen bonds, and apolar interactions. The 4'-phosphopantetheine-acyl chain, which is covalently bound to ACP, interacts with several residues of ISD11, modulating together with ACP the foldability of ISD11. Recombinant human ACP-ISD11 was able to interact with the NFS1 desulfurase, thus yielding an active enzyme, and the NFSI/ACP-ISD11 core complex was activated by frataxin and ISCU proteins. Internal motions of ACP-ISD11 were studied by molecular dynamics simulations, showing the persistence of the interactions between both protein chains. The conformation of the dimer is similar to that found in the context of the (NFS1/ACP-ISD11)(2) supercomplex core, which contains the Escherichia coli ACP instead of the human variant. This fact suggests a sequential mechanism for supercomplex consolidation, in which the ACP-ISD11 complex may fold independently and, after that, the NFS1 dimer would be stabilized.
机译：近年来，哺乳动物线粒体蛋白复合物用于铁 - 硫簇组件一直是重要研究的重点。这部分是因为它在细胞代谢中具有高度相关性，因为所涉及的蛋白质的突变是几种人类疾病的原因。半胱氨酸脱硫酶NFS1是复合物的关键酶。目前，众所周知，通过小蛋白质ISD11稳定NFS1的活性形式。在这项工作中，在2.0分辨率下测定人体线粒体ACP-ISD11异二聚体的结构。 ACP-ISD11形成由几种离子相互作用，氢键和恶性相互作用稳定的协同单元。 4'-磷酸丁乙酰乙酰酰基 - 酰基 - 酰基链环与ACP共价结合，与ISD11的几个残基相互作用，与ACP一起调节ISD11的可折叠性。重组人ACP-ISD11能够与NFS1脱硫酶相互作用，从而产生活性酶，并通过Frataxin和ISCU蛋白激活NFSI / ACP-ISD11核心复合物。通过分子动力学模拟研究了ACP-ISD11的内部运动，显示了两种蛋白质链之间的相互作用的持久性。二聚体的构象类似于（NFS1 / ACP-ISD11）（2）超复合核心的上下文中发现，其含有大肠杆菌ACP而不是人变体。这一事实表明了超复杂合并的顺序机制，其中ACP-ISD11复合物可以独立折叠，然后之后，NFS1二聚体将稳定。

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  • 来源
    《Biochemistry》 |2019年第46期|共14页
  • 作者

    Herrera Maria Georgina; Noguera Martin Ezequiel; Sewel Karl Ellioth; Suarez William Armando Agudelo; Capece Luciana; Klinke Sebastian; Santos Javier;

  • 作者单位

    Univ Buenos Aires Fac Ciencias Exactas &

    Nat Dept Fisiol &

    Biol Mol &

    Celular iB3 Intendente Guiraldes 2160 Ciudad Univ C1428EGA Buenos Aires DF Argentina;

    Univ Buenos Aires Fac Ciencias Exactas &

    Nat Dept Fisiol &

    Biol Mol &

    Celular iB3 Intendente Guiraldes 2160 Ciudad Univ C1428EGA Buenos Aires DF Argentina;

    Univ Buenos Aires Fac Ciencias Exactas &

    Nat Dept Fisiol &

    Biol Mol &

    Celular iB3 Intendente Guiraldes 2160 Ciudad Univ C1428EGA Buenos Aires DF Argentina;

    Fdn Inst Inmunol Colombia FIDIC Av 50 26-20 Bogota Colombia;

    Univ Buenos Aires Dept Quim Inorgan Analit &

    Quim Fis Medio Ambiente &

    Energia INQUIMAE CONICET Inst Quim Fis Mat Fac Ciencias Exactas &

    Nat C1428EGA Buenos Aires DF Argentina;

    IIBBA CONICET Fdn Inst Leloir Av Patricias Argentinas 435 C1405BWE Buenos Aires DF Argentina;

    Univ Buenos Aires Fac Ciencias Exactas &

    Nat Dept Fisiol &

    Biol Mol &

    Celular iB3 Intendente Guiraldes 2160 Ciudad Univ C1428EGA Buenos Aires DF Argentina;

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  • 正文语种 eng
  • 中图分类 生物化学;
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