Direct Activation of Human MLKL by a Select Repertoire of Inositol Phosphate Metabolites.

Journal Article (Journal Article)

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)P4, I(1,3,4,5,6)P5, and IP6 promote membrane permeabilization by MLKL through directly binding the N-terminal executioner domain (NED) and dissociating its auto-inhibitory region. We show that IP6 and inositol pentakisphosphate 2-kinase (IPPK) are required for necroptosis as IPPK deletion ablated IP6 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.

Full Text

Duke Authors

Cited Authors

  • McNamara, DE; Dovey, CM; Hale, AT; Quarato, G; Grace, CR; Guibao, CD; Diep, J; Nourse, A; Cai, CR; Wu, H; Kalathur, RC; Green, DR; York, JD; Carette, JE; Moldoveanu, T

Published Date

  • June 20, 2019

Published In

Volume / Issue

  • 26 / 6

Start / End Page

  • 863 - 877.e7

PubMed ID

  • 31031142

Pubmed Central ID

  • PMC6588482

Electronic International Standard Serial Number (EISSN)

  • 2451-9448

Digital Object Identifier (DOI)

  • 10.1016/j.chembiol.2019.03.010


  • eng

Conference Location

  • United States