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Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization

机译：响应线粒体去极化的帕金依赖泛素化组的景观

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The PARKIN ubiquitin ligase (also known as PARK2) and its regulatory kinase PINK1 (also known as PARK6), often mutated in familial early-onset Parkinson's disease, have central roles in mitochondrial homeostasis and mitophagy. Whereas PARKIN is recruited to the mitochondrial outer membrane (MOM) upon depolarization via PINK1 action and can ubiquitylate porin, mitofusin and Miro proteins on the MOM, the full repertoire of PARKIN substrates-the PARKIN-dependent ubiquitylome-remains poorly defined. Here we use quantitative diGly capture proteomics (diGly) to elucidate the ubiquitylation site specificity and topology of PARKIN-dependent target modification in response to mitochondrial depolarization. Hundreds of dynamically regulated ubiquitylation sites in dozens of proteins were identified, with strong enrichment for MOM proteins, indicating that PARKIN dramatically alters the ubiquitylation status of the mitochondrial proteome. Using complementary interaction proteomics, we found depolarization-dependent PARKIN association with numerous MOM targets, autophagy receptors, and the pro-teasome. Mutation of the PARKIN active site residue C431, which has been found mutated in Parkinson's disease patients, largely disrupts these associations. Structural and topological analysis revealed extensive conservation of PARKIN-dependent ubiquitylation sites on cytoplasmic domains in vertebrate and Drosophila melanogaster MOM proteins. These studies provide a resource for understanding how the PINK1-PARKIN pathway re-sculpts the proteome to support mitochondrial homeostasis.
机译：经常在家族性早发性帕金森氏病中发生突变的PARKIN泛素连接酶（也称为PARK2）及其调节激酶PINK1（也称为PARK6）在线粒体体内稳态和线粒体中起着核心作用。尽管PARKIN在通过PINK1作用去极化时被募集到线粒体外膜（MOM）上，并且可以在MOM上泛素化孔蛋白，线粒体蛋白和Miro蛋白，但PARKIN底物的全部组成部分-依赖PARKIN的泛素化基因组-仍然定义不清。在这里，我们使用定量diGly捕获蛋白质组学（diGly）来阐明响应线粒体去极化的泛素化位点特异性和PARKIN依赖性靶标修饰的拓扑。鉴定了数十种蛋白质中的数百个动态调节的泛素化位点，其中MOM蛋白具有很强的富集性，这表明PARKIN极大地改变了线粒体蛋白质组的泛素化状态。使用互补相互作用蛋白质组学，我们发现去极化依赖的PARKIN与许多MOM靶标，自噬受体和促蛋白酶体相关。在帕金森氏病患者中发现的PARKIN活动位点残基C431的突变大大破坏了这些关联。结构和拓扑分析表明，在脊椎动物和果蝇MOM蛋白的胞质结构域上，PARKIN依赖性泛素化位点具有广泛的保守性。这些研究为理解PINK1-PARKIN途径如何重塑蛋白质组以支持线粒体体内平衡提供了资源。

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  • 来源
    《Nature》 |2013年第7445期|372-376|共5页
  • 作者

    Shireen A. Sarraf; Malavika Raman; Virginia Guarani-Pereira; Mathew E. Sowa; Edward L. Huttlin; Steven P. Gygi; J. Wade Harper;

  • 作者单位

    Department of Cell Biology. Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA;

    Department of Cell Biology. Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA;

    Department of Cell Biology. Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA;

    Department of Cell Biology. Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA;

    Department of Cell Biology. Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA;

    Department of Cell Biology. Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA;

    Department of Cell Biology. Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, 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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