title: Structure of the MST4 in complex with MO25 provides insights into its activation mechanism.
abstract: 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 αC helix of MST4 toward its catalytic core, stabilizing the αC 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.
authors: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Zhubing
authors: Z
authors: Shi
authors: Shi
authors: S
authors: Jiao
authors: Zhen
authors: Z
authors: Zhang
authors: Miao
authors: M
authors: Ma
authors: Zhao
authors: Z
authors: Zhang
authors: Cuicui
authors: C
authors: Chen
authors: Ke
authors: K
authors: Wang
authors: Huizhen
authors: H
authors: Wang
authors: Wenjia
authors: W
authors: Wang
authors: Lei
authors: L
authors: Zhang
authors: Yun
authors: Y
authors: Zhao
authors: Zhaocai
authors: Z
authors: Zhou
mesh_terms: D000818:Animals; D001665:Binding Sites; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000235:genetics; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D004926:Escherichia coli / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D000099317:Hippo Kinases
chemical_list: D002135:Calcium-Binding Proteins; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; C540569:CAB39 protein, human; C430908:STK26 protein, human; D000099317:Hippo Kinases