6VBZ

Crystal structure of the rat MLKL pseudokinase domain

6VBZ の概要

• エントリーDOI: 10.2210/pdb6vbz/pdb
• 分子名称: Mixed lineage kinase domain-like pseudokinase, MANGANESE (II) ION (3 entities in total)
• 機能のキーワード: cell death, necroptosis, pseudokinase, transferase
• 由来する生物種: Rattus norvegicus (Rat)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 66993.85

構造登録者

Davies, K.A.,Czabotar, P.E. (登録日: 2019-12-19, 公開日: 2020-07-08, 最終更新日: 2023-10-11)

主引用文献

Davies, K.A.,Fitzgibbon, C.,Young, S.N.,Garnish, S.E.,Yeung, W.,Coursier, D.,Birkinshaw, R.W.,Sandow, J.J.,Lehmann, W.I.L.,Liang, L.Y.,Lucet, I.S.,Chalmers, J.D.,Patrick, W.M.,Kannan, N.,Petrie, E.J.,Czabotar, P.E.,Murphy, J.M.
Distinct pseudokinase domain conformations underlie divergent activation mechanisms among vertebrate MLKL orthologues.
Nat Commun, 11:3060-3060, 2020

PubMed Abstract: The MLKL pseudokinase is the terminal effector in the necroptosis cell death pathway. Phosphorylation by its upstream regulator, RIPK3, triggers MLKL's conversion from a dormant cytoplasmic protein into oligomers that translocate to, and permeabilize, the plasma membrane to kill cells. The precise mechanisms underlying these processes are incompletely understood, and were proposed to differ between mouse and human cells. Here, we examine the divergence of activation mechanisms among nine vertebrate MLKL orthologues, revealing remarkable specificity of mouse and human RIPK3 for MLKL orthologues. Pig MLKL can restore necroptotic signaling in human cells; while horse and pig, but not rat, MLKL can reconstitute the mouse pathway. This selectivity can be rationalized from the distinct conformations observed in the crystal structures of horse and rat MLKL pseudokinase domains. These studies identify important differences in necroptotic signaling between species, and suggest that, more broadly, divergent regulatory mechanisms may exist among orthologous pseudoenzymes.

PubMed: 32561735
DOI: 10.1038/s41467-020-16823-3

実験手法

X-RAY DIFFRACTION (2.192 Å)