Myelin basic protein (MBP) charge variants show different sphingomyelin-mediated interactions with myelin-like lipid...

Multiple sclerosis (MS) is correlated with increased deimination of myelin basic protein (MBP) in the central nervous system. Here, the interaction of MBP C1 (charge: +19) and MBP C8 (charge: +13) with the major lipids of the cytoplasmic side of the oligodendrocyte membrane is analysed using monolayer adsorption experiments and epifluorescence microscopy. Our findings show that the electrostatic attraction between the positively charged proteins and negatively charged lipids in the myelin-like monolayers competes with the incorporation of MBP into regions directly bordering cholesterol-rich domains. The latter is favoured to avoid additional lipid condensation and reduction in fluidity of the phospholipid layer. We find that MBP C1 does not incorporate at the cholesterol-rich domains if sphingomyelin (SM) is absent from the lipid composition. In contrast, MBP C8 is still incorporated near cholesterol-enriched regions without SM. Thus, the highly charged C1 variant needs a specific interaction with SM, whereas for C8 the incorporation at the cholesterol-rich regions is ensured due to its reduced net positive charge. This phenomenon may be relevant for the correlation of higher amounts of MBP C8 in brains of adult MS patients and healthy children, in which the amount of SM is reduced compared to healthy adults.