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Structural basis of MICAL autoinhibition.
Matej Horvath1,2, Adam Schrofel1,2, Karolina Kowalska1,2
1Department of Cell Biology, Faculty of Science, Charles University, Prague, Czechia.
Nature Communications
|November 12, 2024
Summary
MICAL1 protein activity is regulated by its own structure, specifically an intramolecular interaction that inhibits actin binding. This autoinhibition is overcome by structural changes and binding to other protein domains, controlling cellular dynamics.
Area of Science:
- Molecular and Cellular Biology
- Structural Biology
- Biochemistry
Background:
- Proteins of the MICAL (Molecular Interacting and Coiled-coil domain Containing) family are essential regulators of cellular dynamics, influencing actin filament disassembly.
- MICAL proteins are involved in critical cellular processes including axon guidance, cytokinesis, and maintaining cell morphology, with dysregulation leading to adverse effects.
- Previous research indicated MICALs are autoinhibited and require Rab proteins for activation, but the precise molecular mechanisms were not fully elucidated.
Purpose of the Study:
- To determine the high-resolution cryo-electron microscopy (cryo-EM) structure of human MICAL1.
- To elucidate the molecular mechanisms underlying MICAL1 autoinhibition and activation.
- To investigate the role of intramolecular interactions and domain binding in MICAL1 regulation.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was employed to determine the structure of human MICAL1 at 3.1 Å resolution.
- Biochemical assays were conducted to assess F-actin binding and protein interactions.
- Functional studies were performed to evaluate the impact of structural changes and domain interactions on MICAL1 activity.
Main Results:
- The cryo-EM structure revealed that MICAL1 autoinhibition is mediated by an intramolecular interaction between its N-terminal catalytic domain and C-terminal coiled-coil domain, sterically hindering F-actin binding.
- Allosteric conformational changes within the coiled-coil domain are critical for MICAL1 activation.
- Binding of a tripartite assembly (CH-L2α1-LIM domains) to the coiled-coil domain plays a crucial role in both MICAL1 activation and the release from autoinhibition.
Conclusions:
- MICAL1 is autoinhibited through an intramolecular interaction that blocks its catalytic site from F-actin.
- MICAL1 activation involves allosteric modulation of the coiled-coil domain and specific interactions with the CH-L2α1-LIM complex.
- These regulatory mechanisms appear to be conserved across the MICAL protein family, suggesting a fundamental mode of action in cellular regulation.
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