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Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch

机译：通过磷酸化折叠固有紊乱的蛋白质作为调节开关

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摘要

Intrinsically disordered proteins play important roles in cell signalling, transcription, translation and cell cycle regulation. Although they lack stable tertiary structure, many intrinsically disordered proteins undergo disorder-to-order transitions upon binding to partners. Similarly, several folded proteins use regulated order-to-disorder transitions to mediate biological function. In principle, the function of intrinsically disordered proteins may be controlled by post-trans-lational modifications that lead to structural changes such as folding, although this has not been observed. Here we show that multisite phosphorylation induces folding of the intrinsically disordered 4E-BP2, the major neural isoform of the family of three mammalian proteins that bind eIF4E and suppress cap-dependent translation initiation. In its non-phosphorylated state, 4E-BP2 interacts tightly with eIF4E using both a canonical YXXXXLΦ motif (starting at Y54) that undergoes a disorder-to-helix transition upon binding and a dynamic secondary binding site. We demonstrate that phosphorylation at T37 and T46 induces folding of residues P18-R62 of 4E-BP2 into a four-stranded P-domain that sequesters the helical YXXXXLΦ motif into a partly buried P-strand, blocking its accessibility to eIF4E. The folded state of pT37pT46 4E-BP2 is weakly stable, decreasing affinity by 100-fold and leading to an order-to-disorder transition upon binding to eIF4E, whereas fully phosphorylated 4E-BP2 is more stable, decreasing affinity by a factor of approximately 4,000. These results highlight stabilization of a phosphorylation-induced fold as the essential mechanism for phospho-regulation of the 4E-BP:eIF4E interaction and exemplify a new mode of biological regulation mediated by intrinsically disordered proteins.
机译：本质上无序的蛋白质在细胞信号传导，转录，翻译和细胞周期调节中起重要作用。尽管它们缺乏稳定的三级结构，但许多内在无序的蛋白质在与伴侣结合后会经历从无序到有序的转变。类似地，几种折叠的蛋白质使用调节的有序到无序过渡来介导生物学功能。原则上，内在失调的蛋白质的功能可以通过翻译后修饰来控制，该修饰导致结构变化，例如折叠，尽管尚未观察到。在这里，我们显示多位磷酸化诱导内在无序的4E-BP2折叠，这是结合eIF4E并抑制帽依赖性翻译起始的三种哺乳动物蛋白家族的主要神经同工型。在非磷酸化状态下，4E-BP2使用典型的YXXXXLΦ基序（从Y54开始）与eIF4E紧密相互作用，该基序在结合时会发生从无序到螺旋的转变，并具有动态的二级结合位点。我们证明，在T37和T46处的磷酸化诱导4E-BP2残基P18-R62折叠成四链P结构域，该结构域将螺旋YXXXXLΦ基序隔离成部分埋入的P链，从而阻止了对eIF4E的访问。 pT37pT46 4E-BP2的折叠状态微弱稳定，与eIF4E结合后亲和力降低100倍，并导致有序向无序过渡，而完全磷酸化的4E-BP2则更稳定，使亲和力降低约两倍4,000这些结果强调了磷酸化诱导的折叠的稳定是4E-BP：eIF4E相互作用的磷酸调节的基本机制，并例证了由固有紊乱的蛋白质介导的新的生物调节模式。

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  • 来源
    《Nature》 |2015年第7541期|106-109|共4页
  • 作者

    Alaji Bah; Robert M. Vernon; Zeba Siddiqui; Mickaeel Krzeminski; Ranjith Muhandiram; Charlie Zhao; Nahum Sonenberg; Lewis E. Kay; Julie D. Forman-Kay;

  • 作者单位

    Molecular Structure and Function Program, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada,Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada;

    Molecular Structure and Function Program, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada,Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada;

    Molecular Structure and Function Program, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada;

    Molecular Structure and Function Program, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada,Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada;

    Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada ,Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;

    Molecular Structure and Function Program, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada;

    Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3G 1Y6, Canada;

    Molecular Structure and Function Program, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada,Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada ,Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada,Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada;

    Molecular Structure and Function Program, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada,Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada;

  • 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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