Myelin basic protein (MBP): Membrane adhesion and domain formation
The degradation of central nervous system (CNS) myelin is the hallmark of multiple sclerosis (MS). Increased deimination of MBP, due to aberrant overexpression of peptidylarginine deiminase 2 (PAD2), may represent a primary defect in the disease. The general objectives of this research pertained to the understanding of the functional roles of MBP in CNS myelin both in health and disease. First, it was shown that MBP deimination affected the topological accessibility of an otherwise partially buried key immunodominant epitope of the protein [V83-T92, murine sequence numbering], thereby representing a mechanism by which myelin antigens are released and targeted autoimmune responses are initiated or sustained in MS patients. Second, it was investigated if overexpression of PAD2 in myelinating cells of the CNS, 'in vivo ', can lead to primary demyelination. A transgenic mouse line (PD2), containing multiple copies of MBP-promoter driven PAD2 cDNA, was shown to develop moderate (but significant) clinical, morphological, and biochemical features that were suggestive of mild variants of primary demyelinating disease. Third, MBP was shown to sequester phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2) laterally in model membranes, through cholesterol-dependent non-specific electrostatic interactions, and in a manner sensitive to phosphorylation, deimination, and the binding of Ca2+ bound calmodulin (Ca 2+-CaM). At the cellular level, MBP and PI(4,5)P2 were shown to partially co-localize in cultured oligodendrocytes in punctate domains in the plasma membrane. Moreover, MBP was shown to co-distribute with other PI(4,5)P2 sequestering proteins [myristoylated alanine-rich protein kinase C substrate (MARCKS) and growth associated protein of 43 kDa (GAP-43)] in lipid raft fractions recovered from detergent-extracted isolated myelin and brain homogenates. Thus, MBP may utilitize its high cationicity to promote the formation of PI(4,5)P2-rich signaling platforms involved in cytoskeletal assembly of oligodendrocytes during myelinogenesis. Disruption of these pathways by aberrant post-translational modification of MBP in MS can thereby frustrate inherent attempts at self-repair.