2. Academic Validation
  3. The MLKL kinase-like domain dimerization is an indispensable step of mammalian MLKL activation in necroptosis signaling

The MLKL kinase-like domain dimerization is an indispensable step of mammalian MLKL activation in necroptosis signaling

  • Cell Death Dis. 2021 Jun 22;12(7):638. doi: 10.1038/s41419-021-03859-6.
Yu Zhang 1 2 3,  Jia Liu 1 3,  Dandan Yu 1 3,  Xinxin Zhu 1 2 3,  Xiaoyan Liu 1,  Jun Liao 1,  Sheng Li 4,  Huayi Wang 5
Affiliations

Affiliations

  • 1 School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Pudong, Shanghai, 201210, China.
  • 2 State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
  • 3 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Pudong, Shanghai, 201210, China.
  • 5 School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Pudong, Shanghai, 201210, China. wanghuayi@shanghaitech.edu.cn.
PMID: 34158471 DOI: 10.1038/s41419-021-03859-6
Abstract

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.

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