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Mol Cell. 2016 Feb 18;61(4):589-601. doi: 10.1016/j.molcel.2016.01.011. Epub 2016 Feb 4.

Sequential Engagement of Distinct MLKL Phosphatidylinositol-Binding Sites Executes Necroptosis.

Author information

1
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
2
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
3
Molecular Interaction Analysis Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
4
Cell and Tissue Imaging Center, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
5
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: tudor.moldoveanu@stjude.org.
6
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: douglas.green@stjude.org.

Abstract

Necroptosis is a cell death pathway regulated by the receptor interacting protein kinase 3 (RIPK3) and the mixed lineage kinase domain-like (MLKL) pseudokinase. How MLKL executes plasma membrane rupture upon phosphorylation by RIPK3 remains controversial. Here, we characterize the hierarchical transduction of structural changes in MLKL that culminate in necroptosis. The MLKL brace, proximal to the N-terminal helix bundle (NB), is involved in oligomerization to facilitate plasma membrane targeting through the low-affinity binding of NB to phosphorylated inositol polar head groups of phosphatidylinositol phosphate (PIP) phospholipids. At the membrane, the NB undergoes a "rolling over" mechanism to expose additional higher-affinity PIP-binding sites responsible for robust association to the membrane and displacement of the brace from the NB. PI(4,5)P2 is the preferred PIP-binding partner. We investigate the specific association of MLKL with PIPs and subsequent structural changes during necroptosis.

PMID:
26853145
PMCID:
PMC4769881
DOI:
10.1016/j.molcel.2016.01.011
[Indexed for MEDLINE]
Free PMC Article

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