The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism.


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.

DOI: 10.1016/j.immuni.2013.06.018

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@article{Murphy2013ThePM, title={The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism.}, author={James M. Murphy and Peter E. Czabotar and Joanne M. Hildebrand and Isabelle S Lucet and Zhang Jianguo and Silvia Alvarez-Diaz and Rowena S. Lewis and Najoua Lalaoui and Donald Metcalf and Andrew I. Webb and Samuel N Young and Leila N. Varghese and Gillian Margaret Tannahill and Esme C Hatchell and Ian J. Majewski and Toru Okamoto and Renwick C J Dobson and Douglas J. Hilton and Jeffrey J Babon and Nicos A. Nicola and Andreas Strasser and John Silke and Warren S. Alexander}, journal={Immunity}, year={2013}, volume={39 3}, pages={443-53} }