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Catastrophic disassembly of actin filaments via Mical-mediated oxidation

Elena E Grintsevich1, Peng Ge2, Michael R Sawaya1,3

  • 1Department of Chemistry and Biochemistry, University of California (UCLA), Los Angeles, CA, 90095, USA.

Nature Communications
|December 21, 2017
PubMed

Insights

MICAL-oxidized actin disassembles rapidly, influenced by its nucleotide state. This oxidation, coupled with cofilin, promotes actin filament disassembly regardless of nucleotide binding.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Structural Biology

Background:

  • Actin filament dynamics are crucial for cellular processes.
  • MICAL Redox enzymes modify actin, promoting filament disassembly.
  • Specific oxidation of actin residues M44 and M47 by MICAL enzymes is key.

Purpose of the Study:

  • To investigate the mechanism and dynamics of MICAL-oxidized (Mox) actin disassembly.
  • To elucidate the structural changes induced by MICAL oxidation.
  • To understand the role of Mox-actin in cofilin-mediated filament severing.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) for near-atomic resolution reconstruction.
  • Single-filament total internal reflection fluorescence (TIRF) microscopy.
  • Site-directed mutagenesis to study residue interactions.

Main Results:

  • Mox-actin exhibits extremely fast disassembly (84 subunits/s), dependent on the nucleotide-bound state.
  • Two dynamic and structural states of Mox-actin were identified.
  • Oxidation reorients M44 and creates a M47-O-T351 interaction, destabilizing Mox-actin.
  • Mical oxidation enables cofilin-mediated severing, even with inorganic phosphate present.

Conclusions:

  • MICAL oxidation significantly enhances actin disassembly rates.
  • A novel intermolecular interaction (M47-O-T351) drives Mox-actin instability.
  • MICAL-oxidized actin and cofilin promote F-actin disassembly independently of the nucleotide-bound state.

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