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.