Structure of the MST4 in Complex with MO25 Provides Insights into Its Activation Mechanism
Structure of the MST4 in Complex with MO25 Provides Insights into Its Activation Mechanism
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MST4 与 MO25 复合物的结构为其激活机制提供了见解
DOI：
10.1016/j.str.2013.01.007
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发表时间：
2013-03-05
期刊：
影响因子：
5.7
通讯作者：
Zhou, Zhaocai
中科院分区：
文献类型：
--
作者：
Shi, Zhubing;Jiao, Shi;Zhou, Zhaocai
哺乳动物STE 20样激酶MST 4调节多个细胞方面，如细胞极性和增殖。MST 4在LKB 1/M0 25/STRAD复合物的下游起作用以诱导刷状缘形成。MO 25直接与MST 4相互作用以促进其激酶活性。在这里，我们报告了MST 4与MO 25复合的晶体结构。MO 25的结合使MST 4的α C螺旋向其催化核心旋转，使α C螺旋稳定在活性位置。MST 4的激酶结构域形成反式自磷酸化所需的特异性同源二聚体。MO 25刺激的MST 4活化促进HEK 293 T细胞的凋亡。原子分辨率允许研究能够破坏MST 4-MO 25相互作用或激酶结构域介导的同源二聚化的界面突变。这些突变损害了细胞内MST 4激酶的激活和功能。总之，我们的研究确定了MST 4的激活机制，并为进一步的功能研究提供了结构基础。
Mammalian STE20-like kinase MST4 regulates multiple cellular aspects such as cell polarity and proliferation. MST4 acts downstream of LKB1/MO25/STRAD complex to induce brush border formation. MO25 directly interacts with MST4 to promote its kinase activity. Here, we report the crystal structure of MST4 in complex with MO25. Association of MO25 rotates the alpha C helix of MST4 toward its catalytic core, stabilizing the alpha C helix in an active position. The kinase domain of MST4 forms a specific homodimer that is required for trans-autophosphorylation. MO25-stimulated activation of MST4 promotes apoptosis in HEK293T cells. Atomic resolution permitted the study of interface mutations capable of disrupting the MST4-MO25 interaction or the kinase-domain-mediated homodimerization. These mutations impaired MST4 kinase activation and function within the cell. Collectively, our study identifies the activation mechanism of MST4 and provides a structural basis for further functional study.