A tale of two domains - a structural perspective of the pseudokinase, MLKL.
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.
The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.|Department of Medical Biology, University of Melbourne, Parkville, Vic., Australia.
Peter E
PE
Czabotar
The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.|Department of Medical Biology, University of Melbourne, Parkville, Vic., Australia.
James M
JM
Murphy
D000818:Animals; D017209:Apoptosis; D006801:Humans; D051379:Mice; D009336:Necrosis; D010766:Phosphorylation; D011494:Protein Kinases / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000737:chemistry / Q000502:physiology
C570693:MLKL protein, human; D011494:Protein Kinases; C506249:RIPK1 protein, human; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases
MLKL; RIP1; RIP3; TNF; cell death; four-helix bundle domain; molecular switch; necroptosis; pseudoenzyme; pseudokinase