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Structural basis of MICAL autoinhibition

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.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Pavla Vankova

LAB HEAD: Daniel Rozbesky

PROVIDER: PXD057312 | Pride | 2024-10-30

REPOSITORIES: Pride

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			Action	DRS
	240729_hMICAL1-MO-F-Actin_Results.xlsx	Xlsx
	HDX.zip	Other
	PP_hMICAL1-MO-crap_20240704.fasta	Fasta
	checksum.txt	Txt
	hMICAL-R453C_MO_Peptide-List.xlsx	Xlsx

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