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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The RCAN carboxyl end mediates calcineurin docking-dependent inhibition via a site that dictates binding to substrates and regulators
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The RCAN carboxyl end mediates calcineurin docking-dependent inhibition via a site that dictates binding to substrates and regulators

机译：RCAN羧基末端通过决定与底物和调节剂结合的位点介导钙调神经磷酸酶对接依赖性抑制

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摘要

Specificity of signaling kinases and phosphatases toward their targets is usually mediated by docking interactions with substrates and regulatory proteins. Here, we characterize the motifs involved in the physical and functional interaction of the phosphatase calcineurin with a group of modulators, the RCAN protein family. Mutation of key residues within the hydrophobic docking-cleft of the calcineurin catalytic domain impairs binding to all human RCAN proteins and to the calcineurin interacting proteins Cabin1 and AKAP79. A valine-rich region within the RCAN carboxyl region is essential for binding to the docking site in calcineurin. Although a peptide containing this sequence compromises NFAT signaling in living cells, it does not inhibit calcineurin catalytic activity directly. Instead, calcineurin catalytic activity is inhibited by a motif at the extreme C-terminal region of RCAN, which acts in c/s with the docking motif. Our results therefore indicate that the inhibitory action of RCAN on calcineurin-NFAT signaling results not only from the inhibition of phosphatase activity but also from competition between NFAT and RCAN for binding to the same docking site in calcineurin. Thus, competition by substrates and modulators for a common docking site appears to be an essential mechanism in the regulation of Ca~(2+)-calcineurin signaling.
机译：信号激酶和磷酸酶对其靶标的特异性通常是通过与底物和调节蛋白的对接相互作用来介导的。在这里，我们表征了参与磷酸酶钙调磷酸酶与一组调节剂RCAN蛋白家族的物理和功能相互作用的基序。钙调磷酸酶催化结构域的疏水对接缝内关键残基的突变会削弱与所有人类RCAN蛋白以及钙调磷酸酶相互作用蛋白Cabin1和AKAP79的结合。 RCAN羧基区域内富含缬氨酸的区域对于结合钙调神经磷酸酶的停靠位点至关重要。尽管含有该序列的肽会破坏活细胞中的NFAT信号传导，但它不会直接抑制钙调神经磷酸酶的催化​​活性。取而代之的是，钙调神经磷酸酶的催化​​活性被RCAN极端C末端区域的基序抑制，该基序与对接基序以c / s的方式起作用。因此，我们的结果表明，RCAN对钙调神经磷酸酶-NFAT信号的抑制作用不仅是由于磷酸酶活性的抑制，而且是由于NFAT和RCAN之间竞争结合钙调神经磷酸酶的相同停靠位点而引起的。因此，底物和调节剂对共同停靠位点的竞争似乎是调节Ca〜（2 +）-钙调神经磷酸信号传导的重要机制。

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    Sara Martinez-Martinez; Lali Genesca; Antonio Rodriguez; Alicia Raya; Eulalia Salichs; Felipe Were; Maria Dolores Lopez-Maderuelo; Juan Miguel Redondo; Susana de la Luna;

  • 作者单位

    Department of Vascular Biology and Inflammation, Centra Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain;

    Genes and Disease Program, Centre de Regulacio Genomica, Universitat Pompeu Fabra and CIBER de Enfermedades Raras, 08003 Barcelona, Spain;

    Department of Vascular Biology and Inflammation, Centra Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain Departamento de Biologia Molecular, Facultad de Ciencias, Universidad Autonoma de Madrid, 28049 Madrid, Spain;

    Genes and Disease Program, Centre de Regulacio Genomica, Universitat Pompeu Fabra and CIBER de Enfermedades Raras, 08003 Barcelona, Spain;

    Genes and Disease Program, Centre de Regulacio Genomica, Universitat Pompeu Fabra and CIBER de Enfermedades Raras, 08003 Barcelona, Spain;

    Department of Vascular Biology and Inflammation, Centra Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain;

    Department of Vascular Biology and Inflammation, Centra Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain;

    Department of Vascular Biology and Inflammation, Centra Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain;

    Genes and Disease Program, Centre de Regulacio Genomica, Universitat Pompeu Fabra and CIBER de Enfermedades Raras, 08003 Barcelona, Spain Instituci6 Catalana de Recerca I Estudis Avancats, 08010 Barcelona, Spain;

  • 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

    docking interaction; NFAT; PxIxIT; Cabini; phosphatase;

    机译：对接交互;NFAT;PxIxIT;卡比尼;磷酸酶;

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