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Human RIPK3 maintains MLKL in an inactive conformation prior to cell death by necroptosis.
Meng, Yanxiang; Davies, Katherine A; Fitzgibbon, Cheree; Young, Samuel N; Garnish, Sarah E; Horne, Christopher R; Luo, Cindy; Garnier, Jean-Marc; Liang, Lung-Yu; Cowan, Angus D; Samson, Andre L; Lessene, Guillaume; Sandow, Jarrod J; Czabotar, Peter E; Murphy, James M.
Afiliação
  • Meng Y; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.
  • Davies KA; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Fitzgibbon C; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.
  • Young SN; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Garnish SE; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.
  • Horne CR; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Luo C; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.
  • Garnier JM; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.
  • Liang LY; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Cowan AD; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.
  • Samson AL; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
  • Lessene G; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.
  • Sandow JJ; SYNthesis med chem, 30 Flemington Rd, Parkville, VIC, 3052, Australia.
  • Czabotar PE; Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.
  • Murphy JM; Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
Nat Commun ; 12(1): 6783, 2021 11 22.
Article em En | MEDLINE | ID: mdl-34811356
The 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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Quinases / Morte Celular / Proteína Serina-Treonina Quinases de Interação com Receptores / Necroptose Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Quinases / Morte Celular / Proteína Serina-Treonina Quinases de Interação com Receptores / Necroptose Idioma: En Ano de publicação: 2021 Tipo de documento: Article