6lk6

Publication Abstract from PubMed

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.

The MLKL kinase-like domain dimerization is an indispensable step of mammalian MLKL activation in necroptosis signaling.,Zhang Y, Liu J, Yu D, Zhu X, Liu X, Liao J, Li S, Wang H Cell Death Dis. 2021 Jun 22;12(7):638. doi: 10.1038/s41419-021-03859-6. PMID:34158471^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.