Conformational interconversion of MLKL and disengagement from RIPK3 precede cell death by necroptosis

Garnish, SE; Meng, Y; Koide, A; Sandow, JJ; Denbaum, E; Jacobsen, AV; Yeung, W; Samson, AL; Horne, CR; Fitzgibbon, C; Young, SN; Smith, PPC; Webb, AI; Petrie, EJ; Hildebrand, JM; Kannan, N; Czabotar, PE; Koide, S; Murphy, JM

Author(s): Garnish, SE; Meng, Y; Koide, A; Sandow, JJ; Denbaum, E; Jacobsen, AV; Yeung, W; Samson, AL; Horne, CR; Fitzgibbon, C; Young, SN; Smith, PPC; Webb, AI; Petrie, EJ; Hildebrand, JM; Kannan, N; Czabotar, PE; Koide, S; Murphy, JM;
Details: Publication Year 2021-04-13,Volume 12,Issue #1,Page 2211
Journal Title: Nature Communications
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.
Publisher: NPG
Research Division(s): Inflammation; Structural Biology; Advanced Technology And Biology
PubMed ID: 33850121
Publisher's Version: https://doi.org/10.1038/s41467-021-22400-z
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-021-22400-z
NHMRC Grants: NHMRC/1142669, NHMRC/1079700, NHMRC/1105754, NHMRC/1057905, NHMRC/1124735,
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: Garnish SE et al Nature Comms_2021.pdf - (2.59MB, application/pdf)

Creation Date: 2021-05-11 02:09:47

Last Modified: 2021-05-11 02:16:45