The Structural Basis of Necroptotic Cell Death Signaling

Emma J. Petrie, Peter E. Czabotar, James M. Murphy

Research output: Contribution to journalReview ArticleResearchpeer-review

120 Citations (Scopus)

Abstract

The recent implication of the cell death pathway, necroptosis, in innate immunity and a range of human pathologies has led to intense interest in the underlying molecular mechanism. Unlike the better-understood apoptosis pathway, necroptosis is a caspase-independent pathway that leads to cell lysis and release of immunogens downstream of death receptor and Toll-like receptor (TLR) ligation. Here we review the role of recent structural studies of the core machinery of the pathway, the protein kinases receptor-interacting protein kinase (RIPK)1 and RIPK3, and the terminal effector, the pseudokinase mixed lineage kinase domain-like protein (MLKL), in shaping our mechanistic understanding of necroptotic signaling. Structural studies have played a key role in establishing models that describe MLKL's transition from a dormant monomer to a killer oligomer and revealing important interspecies differences.

Original languageEnglish
Pages (from-to)53-63
Number of pages11
JournalTrends in Biochemical Sciences
Volume44
Issue number1
DOIs
Publication statusPublished - Jan 2019
Externally publishedYes

Keywords

  • cell death
  • DAMPs
  • membrane pore
  • programmed necrosis
  • protein kinase
  • pseudokinase

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