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首页> 外文期刊>The FEBS journal >Mechanism of dual specificity kinase activity of DYRK1A
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Mechanism of dual specificity kinase activity of DYRK1A

机译：DYRK1A双重特异性激酶活性的机制

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摘要

The function of many protein kinases is controlled by the phosphorylation ofa critical tyrosine residue in the activation loop. Dual specificity tyrosinephosphorylation-regulated kinases (DYRKs) autophosphorylate on thistyrosine residue but phosphorylate substrates on aliphatic amino acids. Thisstudy addresses the mechanism of dual specificity kinase activity in DYRK1Aand related kinases. Tyrosine autophosphorylation of DYRK1A occurredrapidly during in vitro translation and did not depend on the non-catalyticdomains or other proteins. Expression in bacteria as well as in mammaliancells revealed that tyrosine kinase activity of DYRK1A is not restricted to theco-translational autophosphorylation in the activation loop. Moreover,mature DYRK1A was still capable of tyrosine autophosphorylation. Pointmutants of DYRK1A and DYRK2 lacking the activation loop tyrosineshowed enhanced tyrosine kinase activity. A series of structurally diverseDYRK1A inhibitors was used to pharmacologically distinguish different conformationalstates of the catalytic domain that are hypothesized to accountfor the dual specificity kinase activity. All tested compounds inhibitedsubstrate phosphorylation with higher potency than autophosphorylationbut none of the tested inhibitors differentially inhibited threonine and tyrosinekinase activity. Finally, the related cyclin-dependent kinase-like kinases(CLKs), which lack the activation loop tyrosine, autophosphorylated ontyrosine both in vitro and in living cells. We propose a model of DYRK autoactivationin which tyrosine autophosphorylation in the activation loop stabilizesa conformation of the catalytic domain with enhanced serine/threoninekinase activity without disabling tyrosine phosphorylation. The mechanismof dual specificity kinase activity probably applies to related serine/threoninekinases that depend on tyrosine autophosphorylation for maturation.
机译：许多蛋白激酶的功能受激活环中关键酪氨酸残基的磷酸化作用控制。双重特异性酪氨酸磷酸化调节激酶（DYRKs）在该酪氨酸残基上自磷酸化，但在脂肪族氨基酸上磷酸化底物。本研究探讨了DYRK1A和相关激酶中双重特异性激酶活性的机制。 DYRK1A的酪氨酸自磷酸化在体外翻译过程中迅速发生，并且不依赖于非催化结构域或其他蛋白质。在细菌以及哺乳动物细胞中的表达表明，DYRK1A的酪氨酸激酶活性不限于激活环中的共翻译自磷酸化。此外，成熟的DYRK1A仍具有酪氨酸自磷酸化能力。缺少激活环酪氨酸的DYRK1A和DYRK2点突变体显示出增强的酪氨酸激酶活性。一系列结构上不同的DYRK1A抑制剂被用于从药理学上区分催化域的不同构象状态，这些状态被认为可解释双重特异性激酶活性。所有测试的化合物都比自磷酸化具有更高的抑制底物磷酸化的能力，但是没有一种测试的抑制剂能够差异地抑制苏氨酸和酪氨酸激酶的活性。最后，相关的细胞周期蛋白依赖性激酶样激酶（CLKs），缺乏激活环酪氨酸，在体外和在活细胞中均自磷酸化了酪氨酸。我们提出了一种DYRK自激活模型，其中激活环中的酪氨酸自磷酸化作用可在不禁用酪氨酸磷酸化的情况下稳定具有增强的丝氨酸/苏氨酸激酶活性的催化结构域的构象。双重特异性激酶活性的机制可能适用于相关的丝氨酸/苏氨酸激酶，这些酶依赖于酪氨酸的自身磷酸化来成熟。

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