Differential Regulation of Myelin Basic Protein Isoforms and Deiminated Isomers by Calmodulin

DURAND E.S.; GALIANO M.R.; BOSC C.; MIRANDA A.L.; FRANK R.; ANDRIEUX A.; HALLAK M.E.

Huerta Grande

Congreso; XXIX annual meeting and SAN-ISN small conference and course; 2014

Sociedad Argentina de Investigación en Neurociencias (SAN)

Myelin basic protein (MBP) is essential for compact myelination of the CNS. MBP interactions with different cellular components are regulated by calmodulin (CaM) and by its post-translational modifications (PTM). We defined 4 different CaM-binding sites (A-D) on MBP isoforms. The binding to CaM of sites A, C and D is Ca2+-dependent, presenting also differential strength of interaction. Site C, which shows the strongest interaction with CaM, has two preserved primary-sequence motifs (KXXK and RXXR) that are present in MBP isoforms 1, 2, 3 and 5. Whereas the alternative splicing that generates the MBP isoforms 4 and 6 presents a site that only preserves the RXXR motif with a weaker interaction with CaM (site D). The relevance of these CaM-binding sites of MBP isoforms 1, 3, 4, 6 and their respective C-terminus truncated mutants (ÄC) was evaluated by co-transfection of cells with CaM cDNA. Considering that the deiminated peptides of the MBP CaM-binding sites have impaired MBP-CaM interaction, our essays also included a mutant of MBP3 (rmC8) to evaluate the effects of deimination, a PTM correlated with multiple sclerosis (MS) pathogenesis. A clear variation of MBP distribution and reduced co-localization with CaM was observed for the ÄC variants of each isoform, showing rmC8 the more significant change. These results suggest that the CaM-binding sites C and D are the major responsible of MBP-CaM interaction, and that the deimination of their arginine residues may account for MS.