The MLKL kinase-like domain dimerization is an indispensable step of mammalian MLKL activation in necroptosis signaling
| Autor: | Xinxin Zhu, Dandan Yu, Yu Zhang, Jun Liao, Xiaoyan Liu, Jia Liu, Sheng Li, Huayi Wang |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Necroptosis Immunology Spodoptera Article Cellular and Molecular Neuroscience Protein Domains Sf9 Cells Animals Humans Direct consequence Phosphorylation X-ray crystallography QH573-671 Necroptosis signaling Chemistry Kinase Cell Biology Cell biology Enzyme Activation HEK293 Cells Receptor-Interacting Protein Serine-Threonine Kinases Colonic Neoplasms Mutation Protein Multimerization Cytology HT29 Cells Protein Kinases Signal Transduction |
| Zdroj: | Cell Death & Disease Cell Death and Disease, Vol 12, Iss 7, Pp 1-9 (2021) |
| ISSN: | 2041-4889 |
| DOI: | 10.1038/s41419-021-03859-6 |
| Popis: | MLKL phosphorylation by RIP3 is the commitment step of necroptosis execution, which could induce MLKL activation featured as MLKL monomer-oligomer transition. Here, we reported that the dimerization of the MLKL kinase-like domain was the direct consequence of RIP3 triggered MLKL-phosphorylation. Two inter-dimer interfaces were found in the crystal structure of human MLKL. Mutations destroying both interfaces could prevent RIP3-induced MLKL oligomerization and necroptosis efficiently. Moreover, we confirmed MLKL self-assembly by the internal coiled-coil region is necessary for MLKL oligomerization and function. The mutations disrupting coiled-coil self-assembly repressed necroptosis, but it did not prevent RIP3-induced dimerization of the MLKL kinase-like domain. So that, MLKL activation is a sequential process, which begins with kinase-like domain dimerization, and followed by internal coiled-coil region self-assembly to form a proper MLKL oligomer. Besides human MLKL, structural and functional analysis showed the kinase-like domain dimerization was conserved among mammalian species, suggesting it is a general step of the RIP3-induced MLKL activation process. |
| Databáze: | OpenAIRE |
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