The linker between SH2 and kinase domains positively regulates catalysis of the Tec family kinases
The linker between SH2 and kinase domains positively regulates catalysis of the Tec family kinases
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DOI：
10.1021/bi602512e
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发表时间：
2007-05-08
期刊：
影响因子：
2.9
通讯作者：
Andreotti, Amy H.
中科院分区：
文献类型：
--
作者：
Joseph, Raji E.;Min, Lie;Andreotti, Amy H.
TEC家族非受体酪氨酸激酶是控制从T细胞和B细胞发育到肌动蛋白细胞骨架重组的各种过程的关键免疫酶。全长Tec激酶一直对结晶具有抵抗力。这种结构数据的缺乏和该激酶家族体外生化数据的缺乏，给我们对Tec激酶调控的理解留下了空白。在这份报告中，我们使用白介素2酪氨酸激酶(ITK)作为一个模型系统，以深入了解Tec激酶的调节机制。体外定量分析发现，ITK的SH2和KK结构域两侧的短链接区在正向调节ITK催化活性中起着重要作用。调节ITK变构的精确残基在Tec激酶中是保守的，表明这种调节机制在家族中是保守的。这些发现表明，Tec激酶的调节方式与Src激酶不同，而是分享了CSK的一些调节特征。
Tec family nonreceptor tyrosine kinases are key immunological enzymes that control processes that range from T and B cell development to reorganization of the actin cytoskeleton. The full-length Tec kinases have been resistant to crystallization. This lack of structural data and the paucity of in vitro biochemical data for this kinase family leave a void in our understanding of Tec kinase regulation. In this report we have used interleukin-2 tyrosine kinase (Itk) as a model system to gain insight into the regulatory apparatus of the Tec kinases. Use of a quantitative in vitro kinase assay has uncovered an essential role for the short linker region flanked by the SH2 and kinase domains of Itk in positively regulating Itk catalytic activity. The precise residues that allosterically regulate Itk are conserved among Tec kinases, pointing to the conserved nature of this regulatory mechanism within the family. These findings indicate that Tec kinases are not regulated in the same manner as the Src kinases but rather share some of the regulatory features of Csk instead.