Human RIPK3 maintains MLKL in an inactive conformation prior to cell death by necroptosis.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 11 2021
22 11 2021
Historique:
received:
29
06
2021
accepted:
29
10
2021
entrez:
23
11
2021
pubmed:
24
11
2021
medline:
29
12
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34811356
doi: 10.1038/s41467-021-27032-x
pii: 10.1038/s41467-021-27032-x
pmc: PMC8608796
doi:
Substances chimiques
Recombinant Proteins
0
MLKL protein, human
EC 2.7.-
MLKL protein, mouse
EC 2.7.-
Protein Kinases
EC 2.7.-
RIPK3 protein, human
EC 2.7.11.1
Receptor-Interacting Protein Serine-Threonine Kinases
EC 2.7.11.1
Ripk3 protein, mouse
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6783Informations de copyright
© 2021. The Author(s).
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