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Phosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization.

Yanxiang Meng1,2, Sarah E Garnish1,2, Katherine A Davies1,2

  • 1Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.

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|October 26, 2023
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Summary

Necroptosis cell death relies on RIPK3 kinase activating MLKL. This study reveals RIPK3 phosphorylation triggers MLKL dimerization and tetramerization, essential for membrane permeabilization and cell death.

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Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Necroptosis is a pro-inflammatory cell death pathway implicated in various human diseases.
  • The terminal steps of necroptosis, involving RIPK3 kinase and MLKL, are not fully understood.

Purpose of the Study:

  • To structurally elucidate the mechanism of MLKL activation by RIPK3.
  • To understand how MLKL oligomerization leads to cell membrane permeabilization.

Main Methods:

  • Negative stain electron microscopy
  • Structural modeling
  • Mutational analysis

Main Results:

  • RIPK3-mediated phosphorylation induces MLKL pseudokinase domain dimerization.
  • MLKL dimerization drives the formation of elongated homotetramers.
  • A central coiled coil within MLKL nucleates tetramer assembly, preceding membrane permeabilization.

Conclusions:

  • MLKL tetramerization is a critical prerequisite for its membrane-disrupting function.
  • Understanding MLKL activation provides insights into necroptosis-related diseases.
  • Structural details reveal the mechanism of MLKL activation by RIPK3 kinase.