PubMed ID: 34545088Ĭellular events require the spatiotemporal interplay between actin assembly and actin disassembly. Profilin and Mical combine to impair F-actin assembly and promote disassembly and remodeling. These results provide a ground state for future work aimed at defining the role of the other domains of Mical - including characterizing their effects on Mical's Redox enzymatic and F-actin disassembly activity. This study provides approaches for obtaining high levels of recombinant protein for the Redox only portion of Mical and demonstrate its catalytic and F-actin disassembly activity. Less is known about the roles of these other MICAL domains. Interestingly, in addition to the MICALs' Redox enzymatic portion through which MICALs covalently modify and affect actin, MICALs have multiple other domains. Furthermore, this MICAL-catalyzed reaction is reversed by another family of Redox enzymes (SelR/MsrB enzymes)-thereby revealing a reversible Redox signaling process and biochemical mechanism regulating actin dynamics. F-actin is a specific substrate for these MICAL Redox enzymes, which oxidize specific amino acids within actin to destabilize actin filaments. This study has identified a family of unusual actin regulators, the MICALs, which are flavoprotein monooxygenase/hydroxylase enzymes that associate with flavin adenine dinucleotide (FAD) and use the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH) in Redox reactions. To change their behaviors, cells require actin proteins to assemble together into long polymers/filaments-and so a critical goal is to understand the factors that control this actin filament (F-actin) assembly and stability. Enhanced Production of the Mical Redox Domain for Enzymology and F-actin Disassembly Assays. These studies identify a stereospecific redox pathway that regulates cardiac physiological and pathological responses to stress across species. Mimicking the effects of M308 oxidation decreased fight-or-flight responses in mice, strikingly impaired heart function in Drosophila melanogaster, and caused disease protection in human induced pluripotent stem cell-derived cardiomyocytes with catecholaminergic polymorphic ventricular tachycardia, a CaMKII-sensitive genetic arrhythmia syndrome. Oxidized or mutant M308 (M308V) decreased CaM binding and CaMKII activity, while absence of MICAL1 in mice caused cardiac arrhythmias and premature death due to CaMKII hyperactivation. MICAL1, a methionine monooxygenase thought to exclusively target actin, and MSRB, a methionine reductase, control the stereospecific redox status of M308, a highly conserved residue in the calmodulin-binding (CaM-binding) domain of CaMKII. This study shows that invertebrates and vertebrates share a common stereospecific redox pathway that protects against pathological responses to stress, at the cost of reduced physiological performance, by constraining Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity. Oxidant stress can contribute to health and disease. MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII. It is concluded that PP2A regulates actin dynamics during dendrite pruning. This change is abolished both upon loss of Mical and PP2A. Moreover, Drosophila cofilin undergoes a change in localization at the onset of metamorphosis indicative of a change in actin dynamics. PP2A interacts genetically with the actin-severing enzymes Mical and cofilin as well as other actin regulators during pruning. ![]() ![]() In a screen for pruning factors, this study identified the protein phosphatase 2 A (PP2A). Dendrite pruning requires local cytoskeleton remodeling, and the actin-severing enzyme Mical is an important ecdysone target. The peripheral sensory class IV dendritic arborization (c4da) neurons of Drosophila larvae specifically prune their dendrites at the onset of metamorphosis in an ecdysone-dependent manner. ![]() Large-scale pruning, the developmentally regulated degeneration of axons or dendrites, is an important specificity mechanism during neuronal circuit formation. PP2A phosphatase is required for dendrite pruning via actin regulation in Drosophila. NCBI links: EntrezGene | Nucleotide | Protein Genetic map position - 3R: 5,828,033.5,868,543 Ĭlassification - Calponin homology domain, Dehydrogenases Keywords - mesoderm, CNS, brain, synaptogenesis, effector of PlexA signaling Gene name - Molecule interacting with CasL
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