Three-dimensional Structure of Myelin Basic Protein

Abstract

A computational model of myelin basic protein (MBP) has been constructed based on the premise of a phylogenetically conserved ␤-sheet backbone and on electron microscopical three-dimensional reconstructions. Many residues subject to post-translational modification (phosphorylation, methylation, or conversion of arginines to citrullines) were located in loop regions and thus accessible to modifying enzymes. The triproline segment (residues 99 -101) is fully exposed on the back surface of the protein in a long crossover connection between two parallel ␤-strands. The proximity of this region to the underlying ␤-sheet suggests that posttranslational modifications here might have potential synergistic effects on the entire structure. Post-translational modifications that lead to a reduced surface charge could result first in a weakened attachment to the myelin membrane rather than in a gross conformational change of the protein itself. Such mechanisms could be operative in demyelinating diseases such as multiple sclerosis. Myelin basic protein (MBP)1 is one of the most important proteins of the myelin sheath (1-6). Its significance is demonstrated in the shiverer mutant of mouse, which has only a small amount of structurally unstable myelin because the gene for MBP is mostly deleted (7,8). This trait is recessive and inherited in a Mendelian manner, indicating that MBP is coded for by a single gene. In mammals, the gene consists of seven exons, and differential splicing of the primary MBP mRNA leads to different isoforms of MBP, i.e. forms of differing molecular weights (9 -11). Alternative splicing of mRNA transcripts is a common mechanism for generating protein diversity. The MBP gene is thus similar to the genes for SV40 T and t antigens, fibrinogen, lens ␣-A crystallin, and troponin T, in all of which primary transcripts with identical termini are alternatively spliced to yield different mature mRNAs (10). The shark MBP gene has also been cloned and has revealed a similar exon structure, indicating that this protein issued early in vertebrate evolution (11).In mammals, the 18.5-and 14-kDa isoforms of MBP are the most common, although the relative proportions vary during development and among species. Henceforth, unless otherwise specified, we shall be using "MBP" to refer to the 18.5-kDa form. Each isoform of MBP can exist as one of many possible charge isomers, due to various post-translational modifications (3, 4). These charge isomers are denoted C1, C2, C3, C4, C5, C6, and C8, according to their elution profile on a cation exchange column at pH 10.5 (12). Component C1 is the least modified and most basic component, while successive components differ sequentially by the loss of a positive charge. Component C8 is an isoform of MBP that does not bind to the resin, and it is the most modified, containing several citrullinyl residues (13). The post-translational modifications include phosphorylation, ADP-ribosylation, and conversion of arginines to citrulline (3,4,13). The latter change is relevant to multiple scl...

Structural Insight into the Function of Myelin Basic Protein as a Ligand for Integrin αMβ2

“…4C) coincided with a peak in disorder probability. A similar finding was made from comparison with the model of the MBP three-dimensional structure by Ridsdale et al (10). In this model, the MBP structure carries a central ␤ sheet with five strands.…”

“…A model of the MBP three-dimensional structure showed that MBP assumes a conformation similar to an open C with a central ␤-sheeted region surrounded by large loop regions rich in charged amino acid residues, which make contact with the cell membrane (10). The model was supported by small angle xray scattering (SAXS) studies of MBP in the presence of lipids and detergents (11).…”

“…For the full ab initio dummy chain model a sequence with the same length of the MBP protein was modeled as dummy residues. For the modeling of the loop regions, the modeling was conducted assuming the presence of a ␤ sheet with five strands in the central core of the molecule (10). Regions of the MBP outside the central ␤ sheet were modeled with dummy residues.…”

Dynamic Imaging of Individual Remyelination Profiles in Multiple Sclerosis

“…Following the pilot demonstration indicating that the stilbene Congo red derivative 1,4‐bis(p‐aminostyryl)‐2‐methoxy benzene, could be used as a myelin tracer suitable for PET imaging,6 a similar affinity for myelin was reported for other stilbene derivatives 7, 8, 9, 10. These tracers, all previously known as amyloid markers, were hypothesized to bind to proteins characterized by a similar conformation contained in amyloid plaques and myelin 11, 12. On this basis, Pittsburgh compound B (PiB), a thioflavin compound binding to amyloid plaques, was also identified as a promising myelin tracer suitable for human PET studies 13.…”

An Immunodominant Epitope of Myelin Basic Protein Is an Amphipathic α-Helix

“…Presently the tertiary structure of MBP is unknown, with the most detailed predictions coming from Martenson (12) and Stoner (13) in the mid-1980s. In these models, as well as in a newer model based upon further research on an electron microscopy single-particle reconstruction, residues 86 -92 are found in a ␤-sheet (14,15). Using [ 1 H]NMR and circular dichroic spectropolarimetry of various MBP peptides with detergent micelles, Mendz et al (16) suggested that there were discrete interaction sites in the protein, one of which could be a helix between residues 87 and 97.…”