Structural dynamics of moonlighting intrinsically disordered proteins - A black box in multiple sclerosis

Multiple Sclerosis (MS) is a demyelinating disease of the central nervous system that disturbs the flow of brain signals to other parts of the body. The actual cause of the disease is still not apparent. The intrinsically disordered proteins (IDP) play a crucial role in neurodegenerative diseases like Alzheimer's, Lewy bodies, Parkinson's, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, etc. In MS, it was known that the immune system attacks the proteins like Myelin Basic Protein (MBP), Myelin-associated Oligodendrocyte Basic protein (MOBP), Myelin-Associated Protein (MAG), and Myelin Proteolipid Protein (PLP) and this leads to demyelination causing MS. Here the proteins MBP and MOBP are both moonlighting intrinsically disordered proteins and exist between the myelin sheath, unlike MAG which is a transmembrane protein. The main focus of the article was to examine the significant role of proteins intrinsically disordered regions (IDR) in maintaining their function. Molecular dynamics simulation studies were performed to study the conformational dynamics of these protein IDRs both in water and near the myelin sheath. The results suggest that the IDR dominates the structural dynamics of these proteins and IDR in both proteins was responsible for their interaction with the myelin sheath. Interestingly, it was noted that the known epitopes MBP_83-96 and MOBP_65-87 in the IDR have no interaction with the myelin sheath. Thus when the protein remains intrinsically disordered it maintains the proper function and myelin integrity and if it adopts folds the region was identified as an epitope by the immune system leading to demyelination causing MS.