Catastrophic disassembly of actin filaments via Mical-mediated oxidation.

Publication Type:

Journal Article


Nat Commun, Volume 8, Issue 1, p.2183 (2017)


Actin Cytoskeleton, Actin Depolymerizing Factors, Actins, Cryoelectron Microscopy, Crystallography, X-Ray, DNA-Binding Proteins, Methionine, Molecular Docking Simulation, Mutagenesis, Site-Directed, Oxidation-Reduction, Protein Binding, Protein Domains, Protein Multimerization, Recombinant Proteins


<p>Actin filament assembly and disassembly are vital for cell functions. MICAL Redox enzymes are important post-translational effectors of actin that stereo-specifically oxidize actin&#39;s M44 and M47 residues to induce cellular F-actin disassembly. Here we show that Mical-oxidized (Mox) actin can undergo extremely fast (84 subunits/s) disassembly, which depends on F-actin&#39;s nucleotide-bound state. Using near-atomic resolution cryoEM reconstruction and single filament TIRF microscopy we identify two dynamic and structural states of Mox-actin. Modeling actin&#39;s D-loop region based on our 3.9&thinsp;Å cryoEM reconstruction suggests that oxidation by Mical reorients the side chain of M44 and induces a new intermolecular interaction of actin residue M47 (M47-O-T351). Site-directed mutagenesis reveals that this interaction promotes Mox-actin instability. Moreover, we find that Mical oxidation of actin allows for cofilin-mediated severing even in the presence of inorganic phosphate. Thus, in conjunction with cofilin, Mical oxidation of actin promotes F-actin disassembly independent of the nucleotide-bound state.</p>