6D74

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

Summary for 6D74

• Entry DOI: 10.2210/pdb6d74/pdb
• NMR Information: BMRB: 30458
• Descriptor: Mixed lineage kinase domain-like protein (1 entity in total)
• Functional Keywords: membrane, lipid binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 18318.13

Authors

Royappa, G.C.,McNamara, D.E.,Moldoveanu, T. (deposition date: 2018-04-24, release date: 2019-05-15, Last modification date: 2024-05-15)

Primary citation

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

Experimental method

SOLUTION NMR