Structure and regulation of the CDK5-p25nck5a complex
Structure and regulation of the CDK5-p25nck5a complex
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DOI：
10.1016/s1097-2765(01)00343-4
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发表时间：
2001-09-01
期刊：
影响因子：
16
通讯作者：
Musacchio, A
中科院分区：
文献类型：
--
作者：
Tarricone, C;Dhavan, R;Musacchio, A
CDK 5在中枢神经系统中起着不可或缺的作用，其失调参与神经退行性变。我们报告的晶体结构的CDK 5和p25，p35激活剂的片段之间的复合物。尽管其部分结构相似的细胞周期蛋白，p25显示了前所未有的机制，调节细胞周期蛋白依赖性激酶。p25将CDK 5的未磷酸化的T环束缚在活性构象中。残基Ser 159相当于CDK 2上的Thr 160，有助于CDK 5-p35相互作用的特异性。它的取代与苏氨酸阻止p35结合，而丙氨酸的存在既不影响结合也不影响激酶活性。最后，我们提供的证据表明，CDK 5-p25复合物采用不同的机制从磷酸-CDK 2-细胞周期蛋白A复合物建立底物特异性。
CDK5 plays an indispensable role in the central nervous system, and its deregulation is involved in neurodegeneration. We report the crystal structure of a complex between CDK5 and p25, a fragment of the p35 activator. Despite its partial structural similarity with the cyclins, p25 displays an unprecedented mechanism for the regulation of a cyclin-dependent kinase. p25 tethers the unphosphorylated T loop of CDK5 in the active conformation. Residue Ser159, equivalent to Thr160 on CDK2, contributes to the specificity of the CDK5-p35 interaction. Its substitution with threonine prevents p35 binding, while the presence of alanine affects neither binding nor kinase activity. Finally, we provide evidence that the CDK5-p25 complex employs a distinct mechanism from the phospho-CDK2-cyclin A complex to establish substrate specificity.