Structure of the catalytic and ubiquitin-associated domains of the protein kinase MARK/Par-1
Structure of the catalytic and ubiquitin-associated domains of the protein kinase MARK/Par-1
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DOI：
10.1016/j.str.2005.09.022
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发表时间：
2006-02-01
期刊：
影响因子：
5.7
通讯作者：
Mandelkow, E
中科院分区：
文献类型：
--
作者：
Panneerselvam, S;Marx, A;Mandelkow, E
丝氨酸/苏氨酸激酶Mark2在阿尔茨海默病神经纤维变性中导致微管脱离的部位磷酸化tau蛋白。Mark2的同源物包括线虫和果蝇中的PAR-1，它会产生胚胎极性。我们报道了人类Mark2的催化结构域和泛素相关结构域(UBA)的X射线结构。该活性被ATP结合位点和/或激活环的突变所改变。催化结构域显示了典型的蛋白激酶的大小叶。在失活和野生型结构中，底物裂隙处于非活性、开放的构象。UBA结构域通过一个紧致的接头连接到激活域的大叶上，并靠在小叶上的疏水斑块上。UBA结构是不寻常的，因为它的第三个螺旋的方向相对于之前的结构是反向的。文中还讨论了该结构对调节激酶活性的可能意义。
The Ser/Thr kinase MARK2 phosphorylates tau protein at sites that cause detachment from microtubules in Alzheimer neurofibrillary degeneration. Homologs of MARK2 include Par-1 in C. elegans and Drosophila, which generates embryonic polarity. We report the X-ray structure of the catalytic and ubiquitin-associated domains (UBA) of human MARK2. The activity was altered by mutations in the ATP binding site and/or activation loop. The catalytic domain shows the small and large lobes typical of kinases. The substrate cleft is in an inactive, open conformation in the inactivated and the wild-type structure. The UBA domain is attached via a taut linker to the large lobe of the kinase domain and leans against a hydrophobic patch on the small lobe. The UBA structure is unusual because the orientation of its third helix is inverted, relative to previous structures. Possible implications of the structure for the regulation of kinase activity are discussed.