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

• Main Authors: Yu Zhang, Jia Liu, Dandan Yu, Xinxin Zhu, Xiaoyan Liu, Jun Liao, Sheng Li, Huayi Wang
• Format: Article
• Language: English
• Published: Nature Publishing Group 2021-06-01
• Series: Cell Death and Disease
• Online Access: https://doi.org/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.