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

Publication ,  Journal Article
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 ...
Published in: Cell Chem Biol
June 20, 2019

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.

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Published In

Cell Chem Biol

DOI

EISSN

2451-9448

Publication Date

June 20, 2019

Volume

26

Issue

6

Start / End Page

863 / 877.e7

Location

United States

Related Subject Headings

  • Spodoptera
  • Sf9 Cells
  • Protein Kinases
  • Inositol Phosphates
  • Humans
  • HT29 Cells
  • Cell Survival
  • Animals
 

Citation

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McNamara, D. E., Dovey, C. M., Hale, A. T., Quarato, G., Grace, C. R., Guibao, C. D., … Moldoveanu, T. (2019). Direct Activation of Human MLKL by a Select Repertoire of Inositol Phosphate Metabolites. Cell Chem Biol, 26(6), 863-877.e7. https://doi.org/10.1016/j.chembiol.2019.03.010
McNamara, Dan E., Cole M. Dovey, Andrew T. Hale, Giovanni Quarato, Christy R. Grace, Cristina D. Guibao, Jonathan Diep, et al. “Direct Activation of Human MLKL by a Select Repertoire of Inositol Phosphate Metabolites.Cell Chem Biol 26, no. 6 (June 20, 2019): 863-877.e7. https://doi.org/10.1016/j.chembiol.2019.03.010.
McNamara DE, Dovey CM, Hale AT, Quarato G, Grace CR, Guibao CD, et al. Direct Activation of Human MLKL by a Select Repertoire of Inositol Phosphate Metabolites. Cell Chem Biol. 2019 Jun 20;26(6):863-877.e7.
McNamara, Dan E., et al. “Direct Activation of Human MLKL by a Select Repertoire of Inositol Phosphate Metabolites.Cell Chem Biol, vol. 26, no. 6, June 2019, pp. 863-877.e7. Pubmed, doi:10.1016/j.chembiol.2019.03.010.
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. Direct Activation of Human MLKL by a Select Repertoire of Inositol Phosphate Metabolites. Cell Chem Biol. 2019 Jun 20;26(6):863-877.e7.

Published In

Cell Chem Biol

DOI

EISSN

2451-9448

Publication Date

June 20, 2019

Volume

26

Issue

6

Start / End Page

863 / 877.e7

Location

United States

Related Subject Headings

  • Spodoptera
  • Sf9 Cells
  • Protein Kinases
  • Inositol Phosphates
  • Humans
  • HT29 Cells
  • Cell Survival
  • Animals