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Autoinhibition and relief mechanisms for MICAL monooxygenases in F-actin disassembly

Author

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  • Leishu Lin

    (Shenzhen Key Laboratory of Biomolecular Assembling and Regulation
    Southern University of Science and Technology)

  • Jiayuan Dong

    (Shenzhen Key Laboratory of Biomolecular Assembling and Regulation
    Southern University of Science and Technology)

  • Shun Xu

    (Shenzhen Key Laboratory of Biomolecular Assembling and Regulation
    Southern University of Science and Technology)

  • Jinman Xiao

    (Southern University of Science and Technology
    and Shenzhen Key Laboratory of Cell Microenvironment)

  • Cong Yu

    (Southern University of Science and Technology
    and Shenzhen Key Laboratory of Cell Microenvironment
    Southern University of Science and Technology)

  • Fengfeng Niu

    (Shenzhen Key Laboratory of Biomolecular Assembling and Regulation
    Southern University of Science and Technology)

  • Zhiyi Wei

    (Shenzhen Key Laboratory of Biomolecular Assembling and Regulation
    Southern University of Science and Technology
    Southern University of Science and Technology)

Abstract

MICAL proteins represent a unique family of actin regulators crucial for synapse development, membrane trafficking, and cytokinesis. Unlike classical actin regulators, MICALs catalyze the oxidation of specific residues within actin filaments to induce robust filament disassembly. The potent activity of MICALs requires tight control to prevent extensive damage to actin cytoskeleton. However, the molecular mechanism governing MICALs’ activity regulation remains elusive. Here, we report the cryo-EM structure of MICAL1 in the autoinhibited state, unveiling a head-to-tail interaction that allosterically blocks enzymatic activity. The structure also reveals the assembly of C-terminal domains via a tripartite interdomain interaction, stabilizing the inhibitory conformation of the RBD. Our structural, biochemical, and cellular analyses elucidate a multi-step mechanism to relieve MICAL1 autoinhibition in response to the dual-binding of two Rab effectors, revealing its intricate activity regulation mechanisms. Furthermore, our mutagenesis study of MICAL3 suggests the conserved autoinhibition and relief mechanisms among MICALs.

Suggested Citation

  • Leishu Lin & Jiayuan Dong & Shun Xu & Jinman Xiao & Cong Yu & Fengfeng Niu & Zhiyi Wei, 2024. "Autoinhibition and relief mechanisms for MICAL monooxygenases in F-actin disassembly," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50940-7
    DOI: 10.1038/s41467-024-50940-7
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    References listed on IDEAS

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