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A tale of two domains – a structural perspective of the pseudokinase, MLKL
Author(s) -
Czabotar Peter E.,
Murphy James M.
Publication year - 2015
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13504
Subject(s) - perspective (graphical) , microbiology and biotechnology , biology , computer science , artificial intelligence
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: RIPK 1, Toll like receptor‐3: TRIF and viral DNA : DAI ( DNA ‐dependent activator of interferon regulatory factors)/ ZBF 1. 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 .