6bwk | pdb_00006bwk
Crystal structure of the human MLKL pseudokinase domain T357E/S358E mutant
Structural highlights
Function[MLKL_HUMAN] Required for the execution of programmed necrosis.[1] Publication Abstract from PubMedNecroptotic cell death is mediated by the most terminal known effector of the pathway, MLKL. Precisely how phosphorylation of the MLKL pseudokinase domain activation loop by the upstream kinase, RIPK3, induces unmasking of the N-terminal executioner four-helix bundle (4HB) domain of MLKL, higher-order assemblies, and permeabilization of plasma membranes remains poorly understood. Here, we reveal the existence of a basal monomeric MLKL conformer present in human cells prior to exposure to a necroptotic stimulus. Following activation, toggling within the MLKL pseudokinase domain promotes 4HB domain disengagement from the pseudokinase domain alphaC helix and pseudocatalytic loop, to enable formation of a necroptosis-inducing tetramer. In contrast to mouse MLKL, substitution of RIPK3 substrate sites in the human MLKL pseudokinase domain completely abrogated necroptotic signaling. Therefore, while the pseudokinase domains of mouse and human MLKL function as molecular switches to control MLKL activation, the underlying mechanism differs between species. Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis.,Petrie EJ, Sandow JJ, Jacobsen AV, Smith BJ, Griffin MDW, Lucet IS, Dai W, Young SN, Tanzer MC, Wardak A, Liang LY, Cowan AD, Hildebrand JM, Kersten WJA, Lessene G, Silke J, Czabotar PE, Webb AI, Murphy JM Nat Commun. 2018 Jun 21;9(1):2422. doi: 10.1038/s41467-018-04714-7. PMID:29930286[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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