Protein kinases are key regulators of cellular processes. MST4, a member of STE20 kinase superfamily, regulates multiple cellular aspects such as cell polarity and proliferation. The scaffold protein MO25 binds and enhances MST4 kinase activity. Recently, researchers from Chinese Academy of Sciences revealed the mechanism of MO25-stimulated MST4 activation.
This study was carried out by researchers led by Prof. ZHOU Zhaocai and Prof. ZHAO Yun at the Shanghai Institute of Biochemistry and Cell Biology, CAS. By determining the structures of the MST4 in complex with MO25 using X-ray diffraction crystallography, and comparison with reported structures of MST4-related kinases, it is found that MO25 binding rotates the αC helix of MST4 towards its catalytic core, stabilizing the αC helix in an active conformation, and the kinase domain of MST4 forms a specific homo-dimer required for trans-autophosphorylation. The detailed interface of MST4 and MO25 was analyzed, and further mutation assays defined the crucial residues for this interaction. MST4 and MO25 complex promotes cell apoptosis in HEK293T cells. Disruption of MST4 association with MO25 or its homo-dimerization impaired MST4 activation and the complex-stimulated apoptosis. These results provide a structural basis for further functional studies of MST4 and other STE20 kinases.
This work entitled “Structure of the MST4 in complex with MO25 provides insights into its activation mechanism” has been published in Structure on March 5th, 2013. It was supported by grants from the Ministry of Science and Technology of China, the National Natural Science Foundation of China, Chinese Academy of Sciences, and the Science and Technology Commission of Shanghai Municipality.
A schematic model of MO25-stimulated MST4 activation. (Image by Prof. ZHOU Zhaocai’s group)
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