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Conformational interconversion of MLKL and disengagement from RIPK3 precede cell death by necroptosis.
- Source :
-
Nature communications [Nat Commun] 2021 Apr 13; Vol. 12 (1), pp. 2211. Date of Electronic Publication: 2021 Apr 13. - Publication Year :
- 2021
-
Abstract
- Phosphorylation of the MLKL pseudokinase by the RIPK3 kinase leads to MLKL oligomerization, translocation to, and permeabilization of, the plasma membrane to induce necroptotic cell death. The precise choreography of MLKL activation remains incompletely understood. Here, we report Monobodies, synthetic binding proteins, that bind the pseudokinase domain of MLKL within human cells and their crystal structures in complex with the human MLKL pseudokinase domain. While Monobody-32 constitutively binds the MLKL hinge region, Monobody-27 binds MLKL via an epitope that overlaps the RIPK3 binding site and is only exposed after phosphorylated MLKL disengages from RIPK3 following necroptotic stimulation. The crystal structures identified two distinct conformations of the MLKL pseudokinase domain, supporting the idea that a conformational transition accompanies MLKL disengagement from RIPK3. These studies provide further evidence that MLKL undergoes a large conformational change upon activation, and identify MLKL disengagement from RIPK3 as a key regulatory step in the necroptosis pathway.
- Subjects :
- Animals
Binding Sites
Cell Membrane
Crystallography, X-Ray
HT29 Cells
Humans
Mice
Molecular Conformation
Molecular Dynamics Simulation
Mutation
Phosphorylation
Protein Conformation
Protein Kinases genetics
Receptor-Interacting Protein Serine-Threonine Kinases genetics
Recombinant Proteins
Sequence Alignment
U937 Cells
Cell Death physiology
Necroptosis physiology
Protein Kinases chemistry
Protein Kinases metabolism
Receptor-Interacting Protein Serine-Threonine Kinases chemistry
Receptor-Interacting Protein Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 12
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 33850121
- Full Text :
- https://doi.org/10.1038/s41467-021-22400-z