1Department of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK.
Sci Signal. 2010 Mar 2;3(111):ra16. doi: 10.1126/scisignal.2000579.
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.
双特异性酪氨酸磷酸化调节激酶（DYRKs）在其激活环中的一个必需酪氨酸残基上自身磷酸化，并在丝氨酸和苏氨酸残基上磷酸化其底物。激活环酪氨酸的磷酸化是分子内发生的，在蛋白质成熟过程中由短暂存在的过渡中间产物介导，并且是 DYRKs 的功能性丝氨酸-苏氨酸激酶活性所必需的。DYRK 家族分为两个亚类。通过生物信息学和突变分析，我们在 2 类 DYRK 的非催化 N 端鉴定出一个保守结构域，该结构域对于激活环酪氨酸的自身磷酸化是必需的，但对于底物中丝氨酸或苏氨酸残基的磷酸化则不是必需的。我们提出，这个结构域，我们称之为 NAPA 结构域，提供了一种伴侣样功能，可将 2 类 DYRK 暂时转化为能够自身磷酸化激活环酪氨酸的分子内激酶。从原生动物到人类的 NAPA 结构域的保守性表明，这种激活环的分子内磷酸化形式是古老的，可能代表了蛋白激酶激活的原始机制。
