Structural Polymorphism and Multifunctionality of Myelin Basic Protein

Abstract

Central nervous system myelin is a dynamic entity arising from membrane processes extended from oligodendrocytes, which form a tightly wrapped multilamellar structure around neurons enabling rapid and efficient signal propagation. The gene of oligodendrocyte lineage (golli) gives rise to a variety of developmentally regulated splice isoforms of myelin basic protein (MBP), denoted golli for early forms and classic for later ones. In mature myelin, the predominant splice isoform of classic MBP is 18.5 kDa; its central role is to maintain the structural integrity of the myelin sheath, by holding together the apposing cytoplasmic leaflets of the oligodendrocyte membrane in a tight, spiral, multilamellar arrangement. This protein's extreme physicochemical properties, net charge of +19 at neutral pH, low proportion of hydrophobic residues, alternating regions of predicted intrinsic disorder and order, induced folding upon association with membranes and other proteins, and diversification via combinatorial post-translational modifications, define not only its role as a molecular Velcro in compact myelin, but as a multifunctional hub that may also bind to a number of other proteins and small molecule ligands in myelinating oligodendrocytes. In particular, MBP may link the underlying cytoskeleton and proteins containing SH3 domains to the membrane, allowing it to transduce transmembrane signals to the cytosol. These associations are facilitated by MBP being an intrinsically disordered protein, creating a large effective protein surface, and by the formation of transient and/or induced ordered secondary structure elements for molecular recognition. These processes can be modulated by a molecular barcode of numerous post-translational modifications and interactions with proteins such as calmodulin. In the human demyelinating disease multiple sclerosis, an aberrant pattern of modifications may contribute to demyelination and confound inherent attempts at repair. The conformational dynamics of the various isoforms and modified variants of MBP and their interactions with other proteins potentially allow them to participate in events coupling extracellular signals to cytoskeletal organization during myelination or remyelination. Various biophysical and cell biological approaches are beginning to elucidate these properties of MBP and are leading to a new understanding of the role of this protein as a linker and/or hub in structural and signaling networks in oligodendrocytes and myelin.

Protein folding at the membrane interface, the structure of Nogo-66 requires interactions with a phosphocholine surface

“…important CNS protein, myelin basic protein (MBP), that becomes helical at the myelin membrane surface (reviewed in ref. 16). Given that protein biological activity most often requires a folded, stable structure, we hypothesize that Nogo-66 adopts a defined structure when bound to the Nogo receptor in activity assays.…”

Myelin Basic Protein synthesis is regulated by small non‐coding RNA 715

“…Alternatively, they may result from reduced MBP levels in response to increased sncRNA715 levels. The importance of MBP for the elaboration of the distinct molecular composition of the oligodendroglial membrane (and myelin) has been demonstrated in detail previously [6] and MBP is associated with the actin and tubulin cytoskeleton [4]. It remains to be shown if sncRNA715 targets the synthesis pathway of other proteins in addition to MBP, which may also lead to the observed effects on cellular morphology and induction of apoptosis.…”

Lipid domains control myelin basic protein adsorption and membrane interactions between model myelin lipid bilayers

“…MBP acts as an intermembrane adhesion protein between the cytoplasmic leaflets of the myelin sheath. The predominant size and charge isoform of MBP in healthy and mature myelin has a molecular weight of 18.5 kDa and a net positive charge of 19 (12,13). Several studies conducted with model and extracted myelin bilayers (9,(14)(15)(16)(17)(18)(19) showed that because of its high content of positively charged residues, MBP binds to the negatively charged lipids of the cytoplasmic leaflets of the bilayer via electrostatic interaction in addition to hydrophobic interactions.…”