8SLZ

Crystal structure of phosphorylated (T357/S358) human MLKL pseudokinase domain

8SLZ の概要

• エントリーDOI: 10.2210/pdb8slz/pdb
• 分子名称: Mixed lineage kinase domain-like protein (2 entities in total)
• 機能のキーワード: pseudokinase, phosphorylation, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32896.71

構造登録者

Meng, Y.,Davies, K.A.,Czabotar, P.E.,Murphy, J.M. (登録日: 2023-04-25, 公開日: 2023-11-08, 最終更新日: 2024-11-06)

主引用文献

Meng, Y.,Garnish, S.E.,Davies, K.A.,Black, K.A.,Leis, A.P.,Horne, C.R.,Hildebrand, J.M.,Hoblos, H.,Fitzgibbon, C.,Young, S.N.,Dite, T.,Dagley, L.F.,Venkat, A.,Kannan, N.,Koide, A.,Koide, S.,Glukhova, A.,Czabotar, P.E.,Murphy, J.M.
Phosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization.
Nat Commun, 14:6804-6804, 2023

PubMed Abstract: The necroptosis pathway is a lytic, pro-inflammatory mode of cell death that is widely implicated in human disease, including renal, pulmonary, gut and skin inflammatory pathologies. The precise mechanism of the terminal steps in the pathway, where the RIPK3 kinase phosphorylates and triggers a conformation change and oligomerization of the terminal pathway effector, MLKL, are only emerging. Here, we structurally identify RIPK3-mediated phosphorylation of the human MLKL activation loop as a cue for MLKL pseudokinase domain dimerization. MLKL pseudokinase domain dimerization subsequently drives formation of elongated homotetramers. Negative stain electron microscopy and modelling support nucleation of the MLKL tetramer assembly by a central coiled coil formed by the extended, ~80 Å brace helix that connects the pseudokinase and executioner four-helix bundle domains. Mutational data assert MLKL tetramerization as an essential prerequisite step to enable the release and reorganization of four-helix bundle domains for membrane permeabilization and cell death.

PubMed: 37884510
DOI: 10.1038/s41467-023-42255-w

実験手法

X-RAY DIFFRACTION (2.3 Å)