The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism

James M Murphy, Peter Edward Czabotar, Joanne M Hildebrand, Isabelle Lucet, Jian-Guo Zhang, Silvia Alvarez-Diaz, Rowena Lewis, Najoua Lalaoui, Donald Metcalf, Andrew Ian Webb, Samuel N Young, Leila N Varghese, Gillian M Tannahill, Esme C Hatchell, Ian J Majewski, Toru Okamoto, Renwick C J Dobson, Douglas Hilton, Jeffrey Babon, Nicos A NicolaAndreas Strasser, John Silke, Warren Alexander

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556 Citations (Scopus)

Abstract

Mixed lineage kinase domain-like (MLKL) is a component of the necrosome, the multiprotein complex that triggers tumor necrosis factor (TNF)-induced cell death by necroptosis. To define the specific role and molecular mechanism of MLKL action, we generated MLKL-deficient mice and solved the crystal structure of MLKL. Although MLKL-deficient mice were viable and displayed no hematopoietic anomalies or other obvious pathology, cells derived from these animals were resistant to TNF-induced necroptosis unless MLKL expression was restored. Structurally, MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation. Structure-guided mutation of the MLKL pseudoactive site resulted in constitutive, RIPK3-independent necroptosis, demonstrating that modification of MLKL is essential for propagation of the necroptosis pathway downstream of RIPK3.
Original languageEnglish
Pages (from-to)443 - 453
Number of pages11
JournalImmunity
Volume39
Issue number3
DOIs
Publication statusPublished - 2013

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