Structure-function studies of MICAL, the unusual multidomain flavoenzyme involved in actin cytoskeleton dynamics

MICAL (from the Molecule Interacting with CasL) indicates a family of multidomain proteins conserved from insects to humans, which are increasingly attracting attention for their participation in the control of actin cytoskeleton dynamics, and, therefore, in the several related key processes in health and disease. MICAL is unique among actin binding proteins because it catalyzes a NADPH-dependent F-actin depolymerizing reaction. This unprecedented reaction is associated with its N-terminal FAD-containing domain that is structurally related to p-hydroxybenzoate hydroxylase, the prototype of aromatic monooxygenases, but catalyzes a strong NADPH oxidase activity in the free state. This review will focus on the known structural and functional properties of MICAL forms in order to provide an overview of the arguments supporting the current hypotheses on the possible mechanism of action of MICAL in the free and F-actin bound state, on the modulating effect of the CH, LIM, and C-terminal domains that follow the catalytic flavoprotein domain on the MICAL activities, as well as that of small molecules and proteins interacting with MICAL.