The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism.
Details
Publication Year 2013-09-19, Volume 39, Issue #3, Page 443-453
Journal Title
Immunity
Publication Type
Journal Article
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.
Publisher
Cell Press
WEHI Research Division(s)
Cancer And Haematology; Molecular Medicine; Structural Biology; Systems Biology And Personalised Medicine; Molecular Genetics Of Cancer; Cell Signalling And Cell Death
Rights Notice
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Creation Date: 2013-09-19 12:00:00
Last Modified: 0001-01-01 12:00:00
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