Crystal structure of the TAO2 kinase domain: activation and specificity of a Ste20p MAP3K.
Crystal structure of the TAO2 kinase domain: activation and specificity of a Ste20p MAP3K.
复制标题
DOI：
10.1016/j.str.2004.07.021
复制
发表时间：
2004-10
期刊：
影响因子：
5.7
通讯作者：
Tianjun Zhou;Malavika Raman;Yan Gao;Svetlana Earnest;Zhu Chen;M. Machius;M. Cobb;E. Goldsmith
中科院分区：
文献类型：
--
作者：
Tianjun Zhou;Malavika Raman;Yan Gao;Svetlana Earnest;Zhu Chen;M. Machius;M. Cobb;E. Goldsmith
TAO 2是一种丝裂原活化蛋白激酶（MAP 3 K），可双重磷酸化并激活MAP激酶激酶（MAP 2K）MEK 3和MEK 6。TAO 2（1-320）的激酶结构域的结构已在其磷酸化活性构象中得到解决。该结构与基于结构的诱变分析一起揭示了底物结合沟中的带正电荷的残基介导MEK 6的双磷酸化的第一步，在MEK 6的基序DS*VAKT*I（* 表示磷酸化位点）中的苏氨酸残基上。TAO 2是一个Ste 20 p同源物，活性TAO 2的结构，与低活性p21激活蛋白激酶（PAK 1），一个Ste 20 p相关的MAP 4K，揭示了这组激酶是如何通过磷酸化激活。最后，活性TAO 2显示与ATP的不寻常的相互作用，部分涉及TAO 2的亚组特异性C-末端延伸。观察到的相互作用可能是有用的，在TAO激酶的特异性抑制剂。
TAO2 is a mitogen-activated protein kinase kinase kinase (MAP3K) that doubly phosphorylates and activates the MAP kinase kinases (MAP2Ks) MEK3 and MEK6. The structure of the kinase domain of TAO2 (1-320) has been solved in its phosphorylated active conformation. The structure, together with structure-based mutagenic analysis, reveals that positively charged residues in the substrate binding groove mediate the first step in the dual phosphorylation of MEK6, on the threonine residue in the motif DS*VAKT*I (*denotes phosphorylation site) of MEK6. TAO2 is a Ste20p homolog, and the structure of active TAO2, in comparison with that of low-activity p21-activated protein kinase (PAK1), a Ste20p-related MAP4K, reveals how this group of kinases is activated by phosphorylation. Finally, active TAO2 displays unusual interactions with ATP, involving, in part, a subgroup-specific C-terminal extension of TAO2. The observed interactions may be useful in making specific inhibitors of TAO kinases.