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Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
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Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis

Published on: August 7, 2018

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Sequential Engagement of Distinct MLKL Phosphatidylinositol-Binding Sites Executes Necroptosis

Giovanni Quarato1, Cliff S Guy1, Christy R Grace2

  • 1Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Molecular Cell
|February 9, 2016
PubMed

Insights

Mixed lineage kinase domain-like (MLKL) oligomerization targets it to the plasma membrane, initiating programmed cell death (necroptosis). Structural changes in MLKL drive membrane association and rupture, a key step in necroptosis.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Necroptosis is a regulated form of cell death.
  • Receptor interacting protein kinase 3 (RIPK3) phosphorylates mixed lineage kinase domain-like (MLKL).
  • The precise mechanism of MLKL-mediated plasma membrane rupture in necroptosis is debated.

Purpose of the Study:

  • To elucidate the structural changes in MLKL during necroptosis.
  • To characterize the mechanism of MLKL's plasma membrane targeting and association.
  • To investigate the role of phosphatidylinositol phosphates (PIPs) in MLKL function.

Main Methods:

  • Structural characterization of MLKL.
  • Biochemical assays to study MLKL-PIP interactions.
  • In vitro studies of MLKL oligomerization and membrane binding.

Main Results:

  • MLKL oligomerization facilitates initial plasma membrane targeting via its N-terminal helix bundle (NB) binding to PIPs.
  • A "rolling over" mechanism of the NB exposes higher-affinity PIP-binding sites for robust membrane association.
  • Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is identified as a preferred PIP-binding partner for MLKL.

Conclusions:

  • MLKL undergoes hierarchical structural changes to execute plasma membrane rupture during necroptosis.
  • The NB plays a dual role in membrane targeting and stabilization through sequential PIP interactions.
  • Understanding MLKL-PIP interactions provides insights into necroptosis execution.

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