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

doi:10.1038/s41419-021-03859-6

	The MLKL kinase-like domain dimerization is an indispensable step of mammalian MLKL activation in necroptosis signaling
	Zhang, Yu1,2,3 ; Liu, Jia1,3 ; Yu, Dandan1,3 ; Zhu, Xinxin1,2,3 ; Liu, Xiaoyan1 ; Liao, Jun1 ; Li, Sheng4 ; Wang, Huayi1
	2021-06-22
发表期刊	CELL DEATH & DISEASE
ISSN	2041-4889
卷号	12 期号:7
DOI	10.1038/s41419-021-03859-6
摘要	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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收录类别	SCIE
语种	英语
WOS研究方向	Cell Biology
WOS类目	Cell Biology
WOS记录号	WOS:000664489400001
出版者	SPRINGERNATURE
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/127564
专题	生命科学与技术学院_硕士生生命科学与技术学院_PI研究组_廖军组生命科学与技术学院_PI研究组_王华翌组生命科学与技术学院_PI研究组_黄行许组免疫化学研究所_特聘教授组_结构生物化学实验室生命科学与技术学院_博士生
通讯作者	Wang, Huayi
作者单位	1.ShanghaiTech Univ, Sch Life Sci & Technol, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China; 2.Chinese Acad Sci, State Key Lab Cell Biol, CAS Ctr Excellence Mol Cell Sci, Shanghai Inst Biochem & Cell Biol,Univ Chinese Ac, Shanghai 200031, Peoples R China; 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 4.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China
第一作者单位	生命科学与技术学院
通讯作者单位	生命科学与技术学院
第一作者的第一单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Zhang, Yu,Liu, Jia,Yu, Dandan,et al. The MLKL kinase-like domain dimerization is an indispensable step of mammalian MLKL activation in necroptosis signaling[J]. CELL DEATH & DISEASE,2021,12(7).
APA	Zhang, Yu.,Liu, Jia.,Yu, Dandan.,Zhu, Xinxin.,Liu, Xiaoyan.,...&Wang, Huayi.(2021).The MLKL kinase-like domain dimerization is an indispensable step of mammalian MLKL activation in necroptosis signaling.CELL DEATH & DISEASE,12(7).
MLA	Zhang, Yu,et al."The MLKL kinase-like domain dimerization is an indispensable step of mammalian MLKL activation in necroptosis signaling".CELL DEATH & DISEASE 12.7(2021).