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

Overview

Journal Cell Chem Biol

Publisher Cell Press

Specialty Biochemistry

Date 2019 Apr 30

PMID 31031142

Citations 26

Authors

Dan E McNamara

Cole M Dovey

Andrew T Hale

Giovanni Quarato

Christy R Grace

Cristina D Guibao

Jonathan Diep

Amanda Nourse

Casey R Cai

Hong Wu

Ravi C Kalathur

Douglas R Green

John D York

Jan E Carette

Tudor Moldoveanu

Affiliations

Soon will be listed here.

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.

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