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  Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis

Petrie, E. J., Sandowl, J. J., Jacobsen V, A., Smith, B. J., Griffin, M. D. W., Lucet, I. S., et al. (2018). Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis. Nature Communications, 9: 2422. doi:10.1038/s41467-018-04714-7.

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 Creators:
Petrie, Emma J.1, Author
Sandowl, Jarrod J.1, Author
Jacobsen V, Annette1, Author
Smith, Brian J.1, Author
Griffin, Michael D. W.1, Author
Lucet, Isabelle S.1, Author
Dai, Weiwen1, Author
Young, Samuel N.1, Author
Tanzer, Maria C.2, Author              
Wardak, Ahmad1, Author
Liang, Lung-Yu1, Author
Cowan, Angus D.1, Author
Hildebrand, Joanne M.1, Author
Kersten, Wilhelmus J. A.1, Author
Lessene, Guillaume1, Author
Silke, John1, Author
Czabotar, Peter E.1, Author
Webb I, Andrew1, Author
Murphy, James M.1, Author
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: MIXED LINEAGE KINASE; ANGLE SCATTERING DATA; STRUCTURAL PERSPECTIVE; MEDIATES NECROPTOSIS; ACTIVATION LOOP; PROTEIN MLKL; MEMBRANE; BINDING; PHOSPHORYLATION; NECROSISScience & Technology - Other Topics;
 Abstract: Necroptotic 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 aC 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.

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Language(s): eng - English
 Dates: 2018
 Publication Status: Published online
 Pages: 15
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 Table of Contents: -
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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 9 Sequence Number: 2422 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723