6D74

Direct Activation of the Executioner Domain of MLKL by a Select Repertoire of Inositol Phosphates

6D74 の概要

• エントリーDOI: 10.2210/pdb6d74/pdb
• NMR情報: BMRB: 30458
• 分子名称: Mixed lineage kinase domain-like protein (1 entity in total)
• 機能のキーワード: membrane, lipid binding protein
• 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: 18318.13

構造登録者

Royappa, G.C.,McNamara, D.E.,Moldoveanu, T. (登録日: 2018-04-24, 公開日: 2019-05-15, 最終更新日: 2024-05-15)

主引用文献

McNamara, D.E.,Dovey, C.M.,Hale, A.T.,Quarato, G.,Grace, C.R.,Guibao, C.D.,Diep, J.,Nourse, A.,Cai, C.R.,Wu, H.,Kalathur, R.C.,Green, D.R.,York, J.D.,Carette, J.E.,Moldoveanu, T.
Direct Activation of Human MLKL by a Select Repertoire of Inositol Phosphate Metabolites.
Cell Chem Biol, 26:863-, 2019

PubMed Abstract: Necroptosis is an inflammatory form of programmed cell death executed through plasma membrane rupture by the pseudokinase mixed lineage kinase domain-like (MLKL). We previously showed that MLKL activation requires metabolites of the inositol phosphate (IP) pathway. Here we reveal that I(1,3,4,6)P, I(1,3,4,5,6)P, and IP promote membrane permeabilization by MLKL through directly binding the N-terminal executioner domain (NED) and dissociating its auto-inhibitory region. We show that IP and inositol pentakisphosphate 2-kinase (IPPK) are required for necroptosis as IPPK deletion ablated IP production and inhibited necroptosis. The NED auto-inhibitory region is more extensive than originally described and single amino acid substitutions along this region induce spontaneous necroptosis by MLKL. Activating IPs bind three sites with affinity of 100-600 μM to destabilize contacts between the auto-inhibitory region and NED, thereby promoting MLKL activation. We therefore uncover MLKL's activating switch in NED triggered by a select repertoire of IP metabolites.

PubMed: 31031142
DOI: 10.1016/j.chembiol.2019.03.010

実験手法

SOLUTION NMR