Structural basis of MICAL autoinhibition

Matej Horvath, Adam Schrofel, Karolina Kowalska, Jan Sabo, Jonas Vlasak, Farahdokht Nourisanami, Margarita Sobol, Daniel Pinkas, Krystof Knapp, Nicola Koupilova, Jiri Novacek, Vaclav Veverka, Zdenek Lansky and Daniel Rozbesky ()
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Matej Horvath: Charles University
Adam Schrofel: Charles University
Karolina Kowalska: Charles University
Jan Sabo: Institute of Biotechnology of the Czech Academy of Sciences
Jonas Vlasak: Charles University
Farahdokht Nourisanami: Charles University
Margarita Sobol: Charles University
Daniel Pinkas: Masaryk University
Krystof Knapp: Charles University
Nicola Koupilova: Charles University
Jiri Novacek: Masaryk University
Vaclav Veverka: Charles University
Zdenek Lansky: Institute of Biotechnology of the Czech Academy of Sciences
Daniel Rozbesky: Charles University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract MICAL proteins play a crucial role in cellular dynamics by binding and disassembling actin filaments, impacting processes like axon guidance, cytokinesis, and cell morphology. Their cellular activity is tightly controlled, as dysregulation can lead to detrimental effects on cellular morphology. Although previous studies have suggested that MICALs are autoinhibited, and require Rab proteins to become active, the detailed molecular mechanisms remained unclear. Here, we report the cryo-EM structure of human MICAL1 at a nominal resolution of 3.1 Å. Structural analyses, alongside biochemical and functional studies, show that MICAL1 autoinhibition is mediated by an intramolecular interaction between its N-terminal catalytic and C-terminal coiled-coil domains, blocking F-actin interaction. Moreover, we demonstrate that allosteric changes in the coiled-coil domain and the binding of the tripartite assembly of CH-L2α1-LIM domains to the coiled-coil domain are crucial for MICAL activation and autoinhibition. These mechanisms appear to be evolutionarily conserved, suggesting a potential universality across the MICAL family.

Date: 2024
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DOI: 10.1038/s41467-024-54131-2

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