TY - JOUR
T1 - The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism
AU - Murphy, James M
AU - Czabotar, Peter Edward
AU - Hildebrand, Joanne M
AU - Lucet, Isabelle
AU - Zhang, Jian-Guo
AU - Alvarez-Diaz, Silvia
AU - Lewis, Rowena
AU - Lalaoui, Najoua
AU - Metcalf, Donald
AU - Webb, Andrew Ian
AU - Young, Samuel N
AU - Varghese, Leila N
AU - Tannahill, Gillian M
AU - Hatchell, Esme C
AU - Majewski, Ian J
AU - Okamoto, Toru
AU - Dobson, Renwick C J
AU - Hilton, Douglas
AU - Babon, Jeffrey
AU - Nicola, Nicos A
AU - Strasser, Andreas
AU - Silke, John
AU - Alexander, Warren
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
UR - http://www.ncbi.nlm.nih.gov/pubmed/24012422
U2 - 10.1016/j.immuni.2013.06.018
DO - 10.1016/j.immuni.2013.06.018
M3 - Article
VL - 39
SP - 443
EP - 453
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 3
ER -