7mon
Structure of human RIPK3-MLKL complexStructure of human RIPK3-MLKL complex
Structural highlights
FunctionMLKL_HUMAN Required for the execution of programmed necrosis.[1] Publication Abstract from PubMedThe ancestral origins of the lytic cell death mode, necroptosis, lie in host defense. However, the dysregulation of necroptosis in inflammatory diseases has led to widespread interest in targeting the pathway therapeutically. This mode of cell death is executed by the terminal effector, the MLKL pseudokinase, which is licensed to kill following phosphorylation by its upstream regulator, RIPK3 kinase. The precise molecular details underlying MLKL activation are still emerging and, intriguingly, appear to mechanistically-diverge between species. Here, we report the structure of the human RIPK3 kinase domain alone and in complex with the MLKL pseudokinase. These structures reveal how human RIPK3 structurally differs from its mouse counterpart, and how human RIPK3 maintains MLKL in an inactive conformation prior to induction of necroptosis. Residues within the RIPK3:MLKL C-lobe interface are crucial to complex assembly and necroptotic signaling in human cells, thereby rationalizing the strict species specificity governing RIPK3 activation of MLKL. Human RIPK3 maintains MLKL in an inactive conformation prior to cell death by necroptosis.,Meng Y, Davies KA, Fitzgibbon C, Young SN, Garnish SE, Horne CR, Luo C, Garnier JM, Liang LY, Cowan AD, Samson AL, Lessene G, Sandow JJ, Czabotar PE, Murphy JM Nat Commun. 2021 Nov 22;12(1):6783. doi: 10.1038/s41467-021-27032-x. PMID:34811356[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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