Structure of MST2 SARAH domain provides insights into its interaction with RAPL |
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| Affiliation: | 1. School of Life Sciences, Anhui University, Hefei, Anhui 230039, China;2. State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;3. National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;4. School of Life Sciences and Technology, Tongji University, Shanghai 200092, China;1. Ultizyme International Ltd., Japan, 1-13-16, Minami, Meguro, Tokyo, 1520013, Japan;2. Department of Biotechnology and Life Science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Japan, 2-24-16, Naka-cho, Koganei, Tokyo, 1848588, Japan;3. Joint Department of Biomedical Engineering, The University of North Carolina at Chapel Hill, North Carolina State University, Chapel Hill, NC, 27599, USA;1. Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA;2. Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA |
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| Abstract: | The STE20 kinases MST1 and MST2 are key players in mammalian Hippo pathway. The SARAH domains of MST1/2 act as a platform to mediate homodimerization and hetero-interaction with a range of adaptors including RASSFs and Salvador, which also possess SARAH domains. Here, we determined the crystal structure of human MST2 SARAH domain, which forms an antiparallel homodimeric coiled coil. Structural comparison indicates that SARAH domains of different proteins may utilize a shared dimerization module to form homodimer or heterodimer. Structure-guided mutational study identified specific interface residues critical for MST2 homodimerization. MST2 mutations disrupting its homodimerization also impaired its hetero-interaction with RAPL (also named RASSF5 and NORE1), which is mediated by their SARAH domains. Further biochemical and cellular assays indicated that SARAH domain-mediated homodimerization and hetero-interaction with RAPL are required for full activation of MST2 and therefore apoptotic functions in T cells. |
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| Keywords: | MST2 RAPL/RASSF5/NORE1 SARAH domain Coiled coil Apoptosis |
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