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Sci Rep. 2016 Mar 3;6:22176. doi: 10.1038/srep22176.

Modulation of MICAL Monooxygenase Activity by its Calponin Homology Domain: Structural and Mechanistic Insights.

Author information

1
Structural Enzymology and Thermodynamics Group, Department of Biophysics &Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 North Wolfe St., Baltimore, MD 21205, USA.
2
Department of Neurology and Department of Biophysics &Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 North Wolfe St., Baltimore, MD 21205, USA.

Abstract

MICALs (Molecule Interacting with CasL) are conserved multidomain enzymes essential for cytoskeletal reorganization in nerve development, endocytosis, and apoptosis. In these enzymes, a type-2 calponin homology (CH) domain always follows an N-terminal monooxygenase (MO) domain. Although the CH domain is required for MICAL-1 cellular localization and actin-associated function, its contribution to the modulation of MICAL activity towards actin remains unclear. Here, we present the structure of a fragment of MICAL-1 containing the MO and the CH domains-determined by X-ray crystallography and small angle scattering-as well as kinetics experiments designed to probe the contribution of the CH domain to the actin-modification activity. Our results suggest that the CH domain, which is loosely connected to the MO domain by a flexible linker and is far away from the catalytic site, couples F-actin to the enhancement of redox activity of MICALMO-CH by a cooperative mechanism involving a trans interaction between adjacently bound molecules. Binding cooperativity is also observed in other proteins regulating actin assembly/disassembly dynamics, such as ADF/Cofilins.

PMID:
26935886
PMCID:
PMC4792234
DOI:
10.1038/srep22176
[Indexed for MEDLINE]
Free PMC Article

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