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A plug release mechanism for membrane permeation by MLKL

Lijing Su1, Bradley Quade1, Huayi Wang2

  • 1Department of Biophysics, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.

Structure (London, England : 1993)
|September 16, 2014
PubMed

Insights

The mixed lineage kinase domain-like (MLKL) protein

Area of Science:

  • Molecular Biology
  • Cell Death Research
  • Structural Biology

Background:

  • Mixed lineage kinase domain-like (MLKL) is essential for necroptosis, a programmed cell death pathway.
  • MLKL's N-terminal region is responsible for membrane permeabilization, but the exact mechanism remains unclear.

Purpose of the Study:

  • To elucidate the structural mechanism by which the MLKL N-terminal region permeabilizes membranes during necroptosis.

Main Methods:

  • Nuclear magnetic resonance (NMR) spectroscopy to determine the solution structure of the MLKL N-terminal region.
  • Fluorescence spectroscopy to study membrane interactions and liposome leakage assays.

Main Results:

  • The MLKL N-terminal region forms a unique six-helix bundle structure.
  • The four-helix bundle core inserts into membranes and induces liposome leakage.
  • A C-terminal helix (helix 6) acts as an inhibitory plug, preventing bundle opening.

Conclusions:

  • The four-helix bundle of MLKL directly mediates membrane breakdown during necroptosis.
  • Phosphorylation by RIP3 likely releases the inhibitory C-terminal helix, activating MLKL for membrane permeabilization.

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