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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Identification of the phosphorylation sites on the E3 ubiquitin ligase Pellino that are critical for activation by IRAK1 and IRAK4
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Identification of the phosphorylation sites on the E3 ubiquitin ligase Pellino that are critical for activation by IRAK1 and IRAK4

机译：鉴定E3泛素连接酶Pellino上对IRAK1和IRAK4激活至关重要的磷酸化位点

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摘要

The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1 similarly with any of several E2-conjugating enzymes (Ubc13-Uev1a, UbcH4, or UbcH5a/5b) and identify 7 amino acid residues in Pellino 1 whose phosphorylation is critical for activation. Five of these sites are clustered between residues 76 and 86 (Ser-76, Ser-78, Thr-80, Ser-82, and Thr-86) and decorate a region of antiparallel β-sheet, termed the "wing," which is an appendage of the forkhead-associated domain that is thought to interact with IRAK1. The other 2 sites are located at Thr-288 and Ser-293, just N-terminal to the RING-like domain that carries the E3 ligase activity. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). These observations imply that dephos-phorylation of multiple sites is required to inactivate Pellino 1, which could be a device for prolonging Pellino's E3 ubiquitin ligase activity in vivo.
机译：E3泛素连接酶Pellino可以通过IL-1受体相关激酶1（IRAK1）或IRAK4的体外磷酸化激活。在这里，我们发现磷酸化增强了Pellino 1的E3连接酶活性，与几种E2偶联酶（Ubc13-Uev1a，UbcH4或UbcH5a / 5b）类似，并鉴定了Pellino 1中的7个氨基酸残基，其磷酸化对于激活至关重要。这些位点中的五个聚集在残基76和86之间（Ser-76，Ser-78，Thr-80，Ser-82和Thr-86），并装饰了一个反平行的β-折叠区域，称为“翅膀”，是叉头相关域的附件，被认为与IRAK1交互。其他2个位点位于Thr-288和Ser-293，仅在携带E3连接酶活性的RING样结构域的N端。通常，Pellino 1的完全活化可以通过将几个不同位点（Ser-76，Thr-86，Thr-288或Ser-293）中的任何一个或其他位点（Ser-78，Thr- 80和Ser-82）。这些观察结果表明，需要多个位点的去磷酸化才能使Pellino 1失活，这可能是延长Pellino E3泛素连接酶在体内活性的一种装置。

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  • 作者

    Hilary Smith; Mark Peggie; David G. Campbell; Franck Vandermoere; Emma Carrick; Philip Cohen; Emma Carrick;

  • 作者单位

    Medical Research Council Protein Phosphorylation Unit, The Sir James Black Centre, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland;

    Medical Research Council Protein Phosphorylation Unit, The Sir James Black Centre, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland;

    Medical Research Council Protein Phosphorylation Unit, The Sir James Black Centre, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland;

    Medical Research Council Protein Phosphorylation Unit, The Sir James Black Centre, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland;

    Medical Research Council Protein Phosphorylation Unit, The Sir James Black Centre, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland;

    Medical Research Council Protein Phosphorylation Unit, The Sir James Black Centre, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland;

    Medical Research Council Protein Phosphorylation Unit, The Sir James Black Centre, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    toll-like receptor; innate immunity; lysine63-linked polyubiquitination;

    机译：收费型受体先天免疫;赖氨酸63连接的多泛素化;

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