PDBsum entry 6bwk

Transferase

PDB id: 6bwk

Contents

Protein chain

263 a.a.

Ligands

GOL ×4

Waters ×4

PDB id:

6bwk

Name:

Transferase

Title:

Crystal structure of the human mlkl pseudokinase domain t357e/s358e mutant

Structure:

Mixed lineage kinase domain-like protein. Chain: a. Fragment: unp residues 190-471. Synonym: hmlkl. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mlkl. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.79Å R-factor: 0.257 R-free: 0.297

Authors:

A.D.Cowan,P.E.Czabotar,J.M.Murphy

Key ref:

E.J.Petrie et al. (2018). Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis. Nat Commun, 9, 2422. PubMed id: 29930286

Date:

15-Dec-17 Release date: 27-Jun-18

Protein chain

Q8NB16  (MLKL_HUMAN) -  Mixed lineage kinase domain-like protein from Homo sapiens

Seq: 471 a.a.

Struc: 263 a.a.

Nat Commun 9:2422 (2018)

PubMed id: 29930286

Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis.

E.J.Petrie, J.J.Sandow, A.V.Jacobsen, B.J.Smith, M.D.W.Griffin, I.S.Lucet, W.Dai, S.N.Young, M.C.Tanzer, A.Wardak, L.Y.Liang, A.D.Cowan, J.M.Hildebrand, W.J.A.Kersten, G.Lessene, J.Silke, P.E.Czabotar, A.I.Webb, J.M.Murphy.

ABSTRACT

Necroptotic cell death is mediated by the most terminal known effector of the pathway, MLKL. Precisely how phosphorylation of the MLKL pseudokinase domain activation loop by the upstream kinase, RIPK3, induces unmasking of the N-terminal executioner four-helix bundle (4HB) domain of MLKL, higher-order assemblies, and permeabilization of plasma membranes remains poorly understood. Here, we reveal the existence of a basal monomeric MLKL conformer present in human cells prior to exposure to a necroptotic stimulus. Following activation, toggling within the MLKL pseudokinase domain promotes 4HB domain disengagement from the pseudokinase domain αC helix and pseudocatalytic loop, to enable formation of a necroptosis-inducing tetramer. In contrast to mouse MLKL, substitution of RIPK3 substrate sites in the human MLKL pseudokinase domain completely abrogated necroptotic signaling. Therefore, while the pseudokinase domains of mouse and human MLKL function as molecular switches to control MLKL activation, the underlying mechanism differs between species.