MICAL1 Monooxygenase in Autosomal Dominant Lateral Temporal Epilepsy: Role in Cytoskeletal Regulation and Relation to Cancer

Abstract

Autosomal dominant lateral temporal epilepsy (ADLTE) is a genetic focal epilepsy associated with mutations in the LGI1, RELN, and MICAL1 genes. A previous study linking ADLTE with two MICAL1 mutations that resulted in the substitution of a highly conserved glycine residue for serine (G150S) or a frameshift mutation that swapped the last three C-terminal amino acids for 59 extra residues (A1065fs) concluded that the mutations increased enzymatic activity and promoted cell contraction. The roles of the Molecule Interacting with CasL 1 (MICAL1) protein in tightly regulated semaphorin signaling pathways suggest that activating MICAL1 mutations could result in defects in axonal guidance during neuronal development. Further studies would help to illuminate the causal relationships of these point mutations with ADLTE. In this review, we discuss the proposed pathogenesis caused by mutations in these three genes, with a particular emphasis on the G150S point mutation discovered in MICAL1. We also consider whether these types of activating MICAL1 mutations could be linked to cancer.

MICAL-mediated oxidation of actin and its effects on cytoskeletal and cellular dynamics

“…Below we provide a general overview of what is known of the MICAL's in vivo functions. For additional coverage including detailed specifics of the MICAL's in vivo functions, we refer readers to Wilson et al, 2016;Manta and Gladyshev, 2017;Vanoni, 2017;Alto and Terman, 2018;Ortegón Salas et al, 2020;Haikazian and Olson, 2022;Rouyère et al, 2022).…”

Autoinhibition and Activation Mechanisms for MICAL Monooxygenases in F-actin Disassembly

“…5i). Additionally, it is noteworthy that a disease-associated frame-shifting mutant A1065fs, which lengthens the H3 helix with an excess of 59 amino acids, boosted MICAL1's activity in cells 27,42 , further confirming the crucial role of H3 in regulating the autoinhibition and activation of MICAL1.…”

MICAL1 in Tumour Cell Motility

“…These enzymes have specificity for oxidized methionine and catalyze the reduction back to methionine (18). Research suggests that MICAL1 forms a catalytic loop around F-actin from amino acids 395 to 405 (19). MICAL1 binding to F-actin induces a conformational change at tryptophan position 400 which is thought to promote the transferring of NADPH to FAD, to facilitate hydrogen peroxide formation (19).…”