A tale of two domains - a structural perspective of the pseudokinase, MLKL

The FEBS Journal
Peter E Czabotar, J M Murphy

Abstract

Recently, the programmed necrosis or 'necroptosis' cell death pathway has attracted much interest because of its implication in multiple pathologies, including inflammatory diseases and the cell death arising from ischaemia reperfusion injuries. Pharmacologically, necroptosis is an attractive target because, unlike the counterpart pathway, apoptosis, it is dispensable for mammalian development. In particular, the most terminal-known obligate effector in the necroptosis pathway, the pseudokinase MLKL (mixed lineage kinase domain-like), holds particular appeal because, thus far, its only known function is as a mediator of necroptotic cell death. We review the current understanding and gaps in knowledge relating to how MLKL can be activated by receptor interacting protein kinase (RIPK)3 downstream of tumour necrosis factor receptor 1:RIPK1, Toll like receptor-3:TRIF and viral DNA: DAI (DNA-dependent activator of interferon regulatory factors)/ZBF1. We also discuss the potential mechanism(s) by which MLKL induces necroptotic cell death, with particular emphasis on insights arising from structural studies of mouse and human MLKL.

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Citations

Feb 13, 2016·Cell Death and Differentiation·M C TanzerJ M Murphy
Dec 15, 2015·The FEBS Journal·Seamus J Martin
Dec 22, 2016·Immunology and Cell Biology·Emma J PetrieJames M Murphy
Nov 22, 2015·Bioscience Reports·Henrik Maximilian HammarénOlli Silvennoinen
Sep 26, 2020·Frontiers in Medicine·Francisco IdalsoagaJuan Pablo Arab
May 19, 2019·Cell Death and Differentiation·Snahel PatelDomagoj Vucic
Oct 8, 2020·The FEBS Journal·Colin Adrain

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis