![]() The regions corresponding to the actin binding site (ABS) of type 2 calponin homology (CH2) domains and to the phosphatidylinositol (4,5)-bisphosphate (PIP2) binding site also found in type 2 CH domains are also indicated. In the CH domain, residues forming the hydrophobic core as based on the structure of the CH domain of human MICAL1 (PDB ID 2DK9, ) are underlined. The conserved regions of MICAL’s MO domain are indicated with the red stars below the aligned sequences as in. In plain characters are those identified by us as also contributing to the formation of the patch of basic potential for NADPH binding. Red, residues proposed to be involved in the interaction with NADPH as deduced from the comparison with PHBH and structural analysis. The residues matching the ADP binding region identified as in and those matching the second FAD consensus sequence identified based on are in bold the additional residues that interact with the isoalloxazine ring (i), the pyrophosphate (p), adenosine (Ado) and AMP regions of FAD, as identified in, are also indicated. Yellow, residues implicated in FAD binding as specified above the sequences. and those identified by us from sequence and structural comparisons. In bold are conserved residues identified by Nadella et al. A: cyan, basic residues in the N-terminal proteins regions forming one of the patches of basic potential on MICAL-MO. The sequences were annotated as follows, with the numbering of mouse MICAL1. The output reflects the degree of sequence similarity among the proteins. Regions corresponding to the monooxygenase (MO) and calponin homology (CH) domains ( A), LIM domain ( B), Pro-rich ( C), Glu-rich ( D) and C-terminal coiled-coil regions ( E) of selected MICAL sequences (Table 1) have been aligned with ClustalW2. Arguments supporting the concept that MICAL effect on F-actin may be reversible will be discussed. ![]() With Drosophila MICAL forms, actin depolymerization was demonstrated to be associated to conversion of Met44 to methionine sulfone through a postulated hydroxylating reaction. This review focuses on the structure-function relations of the MICAL monooxygenase-like domain as they are emerging from the available in vitro studies on mouse, human and Drosophila MICAL forms that demonstrated a NADPH-dependent actin depolymerizing activity of MICAL. Genetic and cell biology approaches have demonstrated an essential role of the catalytic activity of the monooxygenase-like domain in transducing the signal initiated by semaphorins interaction with their plexin receptors, which results in local actin cytoskeleton disassembly as part of fundamental processes that include differentiation, migration and cell-cell contacts in neuronal and non-neuronal cell types. MICAL (from the Molecule Interacting with CasL) indicates a family of recently discovered cytosolic, multidomain proteins, which uniquely couple an N-terminal FAD-containing monooxygenase-like domain to typical calponine homology, LIM and coiled-coil protein-interaction modules.
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