Characterization of a Domain that Transiently Converts Class 2 DYRKs into Intramolecular Tyrosine Kinases
Characterization of a Domain that Transiently Converts Class 2 DYRKs into Intramolecular Tyrosine Kinases
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DOI：
10.1126/scisignal.2000579
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发表时间：
2010-03-02
影响因子：
7.3
通讯作者：
Cleghon, Vaughn
中科院分区：
文献类型：
--
作者：
Kinstrie, Ross;Luebbering, Nathan;Cleghon, Vaughn
双特异性酪氨酸磷酸化调节激酶（DYRKs）在其活化环中自磷酸化必需的酪氨酸残基，并磷酸化其丝氨酸和苏氨酸残基上的底物。激活环酪氨酸的磷酸化发生在分子内，由蛋白质成熟期间的短暂过渡中间体介导，并且是DYRKs的功能性丝氨酸-苏氨酸激酶活性所需的。DYRK家族分为两个子类。通过生物信息学和突变分析，我们确定了一个保守的结构域的非催化N末端的2类DYRK的活化环酪氨酸的自磷酸化所需的，但不为底物中的丝氨酸或苏氨酸残基的磷酸化。我们建议，这个域，我们称之为NAPA域，提供了一个伴侣样的功能，瞬时转换2类DYRKs到分子内激酶能够自磷酸化的激活环酪氨酸。从锥虫到人类的NAPA结构域的保守性表明，这种形式的激活环的分子内磷酸化是古老的，可能代表了蛋白激酶激活的原始机制。
Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) autophosphorylate an essential tyrosine residue in their activation loop and phosphorylate their substrates on serine and threonine residues. Phosphorylation of the activation loop tyrosine occurs intramolecularly, is mediated by a short-lived transitional intermediate during protein maturation, and is required for functional serine-threonine kinase activity of DYRKs. The DYRK family is separated into two subclasses. Through bioinformatics and mutational analyses, we identified a conserved domain in the noncatalytic N terminus of a class 2 DYRK that was required for autophosphorylation of the activation loop tyrosine but not for the phosphorylation of serine or threonine residues in substrates. We propose that this domain, which we term the NAPA domain, provides a chaperone-like function that transiently converts class 2 DYRKs into intramolecular kinases capable of autophosphorylating the activation loop tyrosine. The conservation of the NAPA domain from trypanosomes to humans indicates that this form of intramolecular phosphorylation of the activation loop is ancient and may represent a primordial mechanism for the activation of protein kinases.