8Y6K

Cryo-EM structure of full-length MICAL1 in the autoinhibited state

Summary for 8Y6K

• Entry DOI: 10.2210/pdb8y6k/pdb
• EMDB information: 38989
• Descriptor: [F-actin]-monooxygenase MICAL1, ZINC ION, FLAVIN-ADENINE DINUCLEOTIDE (3 entities in total)
• Functional Keywords: mical1, monooxygenase, f-actin disassembly, autoinhibition, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 118931.10

Authors

Niu, F.,Wei, Z. (deposition date: 2024-02-02, release date: 2024-08-28, Last modification date: 2024-09-25)

Primary citation

Lin, L.,Dong, J.,Xu, S.,Xiao, J.,Yu, C.,Niu, F.,Wei, Z.
Autoinhibition and relief mechanisms for MICAL monooxygenases in F-actin disassembly.
Nat Commun, 15:6824-6824, 2024

PubMed 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.

PubMed: 39122694
DOI: 10.1038/s41467-024-50940-7

Experimental method

ELECTRON MICROSCOPY (3.94 Å)