The Classic Basic Protein of Myelin–Conserved Structural Motifs and the Dynamic Molecular Barcode Involved in Membrane Adhesion, Protein-Protein Interactions, and Pathogenesis in Multiple Sclerosis

The myelin basic protein (MBP) family comprises a variety of developmentally-regulated members arising from different transcription start sites, differential splicing, and post-translational modifications. The “classic” isoforms of MBP include the 18.5-kDa form, which predominates in adult human myelin and facilitates compaction of the mature myelin sheath in the central nervous system, thereby maintaining its structural integrity. In addition to membrane-association, the 18.5-kDa and all other classic isoforms are able to interact with a multitude of proteins, including Ca²⁺-calmodulin, actin, tubulin, and SH3-domain-containing proteins, and thus may be signalling linkers during myelin development and remodelling. All proteins in this family are intrinsically disordered, creating a large effective surface to facilitate multiple protein associations, and are post-translationally modified to various degrees by methylation, phosphorylation, and deimination. We have used spectroscopic (fluorescence, circular dichroism, electron paramagnetic resonance, and nuclear magnetic resonance) and computational (molecular dynamics) approaches to study MBP’s conformational adaptability. A highly-conserved central domain consists of an amphipathic α-helix that associates with a phospholipid membrane. In multiple sclerosis, this segment represents a primary immunodominant epitope. This α-helical structure is adjacent to a proline-rich region that contains a classic SH3-ligand along with two threonyl MAP-kinase phosphorylation sites, and forms a poly-proline type II (PPII) structure. This α-helical segment of the protein is thus essential to proper positioning of the PPII protein-interaction motif, with the local conformation and accessibility being modulated by MAP-kinases, and may represent an important molecular switch. Aberrant post-translational or other modifications in this segment of the protein may participate in the onset and pathogenesis of the human demyelinating disease multiple sclerosis.

Keywords: Myelin, oligodendrocyte, myelin basic protein, multiple sclerosis, intrinsically-disordered protein, molecular recognition fragments (MoRFs), Golli (genes of oligodendrocyte lineage), membrane adhesion, membrane microdomains, amphipathic α-helix, poly-proline type II (PPII) conformation, SH3-domain, phosphorylation, deimination, post-translational modifications, molecular barcode, CD (circular dichroism) spectroscopy, EPR (electron paramagnetic resonance) spectroscopy, NMR (nuclear magnetic resonance) spectroscopy, molecular dynamics (MD) simulations.