4BTF

Structure of MLKL

Summary for 4BTF

• Entry DOI: 10.2210/pdb4btf/pdb
• Descriptor: MIXED LINEAGE KINASE DOMAIN-LIKE PROTEIN, FORMIC ACID, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: transferase, pseduokinase, necroptosis
• Biological source: MUS MUSCULUS (HOUSE MOUSE)
• Total number of polymer chains: 1
• Total formula weight: 54026.95

Authors

Czabotar, P.E.,Murphy, J.M. (deposition date: 2013-06-16, release date: 2013-09-18, Last modification date: 2024-05-08)

Primary citation

Murphy, J.M.,Czabotar, P.E.,Hildebrand, J.M.,Lucet, I.S.,Zhang, J.-G.,Alvarez-Diaz, S.,Lewis, R.,Lalaoui, N.,Metcalf, D.,Webb, A.I.,Young, S.N.,Varghese, L.N.,Tannahill, G.M.,Hatchell, E.C.,Majewski, I.J.,Okamoto, T.,Dobson, R.C.J.,Hilton, D.J.,Babon, J.J.,Nicola, N.A.,Strasser, A.,Silke, J.,Alexander, W.S.
The Pseudokinase Mlkl Mediates Necroptosis Via a Molecular Switch Mechanism
Immunity, 39:443-, 2013

PubMed 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.

PubMed: 24012422
DOI: 10.1016/J.IMMUNI.2013.06.018

Experimental method

X-RAY DIFFRACTION (2.604 Å)