Prediction of the Secondary Structure of Myelin Basic Protein

Martenson, Russell E.

doi:10.1111/j.1471-4159.1981.tb00598.x

Cited by 55 publications

(56 citation statements)

References 76 publications

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“…It has been proposed that these charged groups interact electrostatically with the negatively charged inner face of the membrane during insertion of the protein into the membrane, thereby anchoring the cluster and preventing it from passing through (14). A second argument is that El and E3 are remarkably similar, in terms of amino acid sequence (36% homology) and predicted secondary structure to the myelin basic protein, which appears to be located entirely on the cytoplasmic side of the membrane (5,15,16). Finally, there is evidence (see below) that Cl and the region E2 + C3 + C3' contain disulfide bonds and are therefore likely to be located in and on the outer leaflet of the cell membrane bilayer (17).…”

Section: Resultsmentioning

confidence: 99%

The structure of bovine brain myelin proteolipid and its organization in myelin.

Laursen¹,

Samiullah²,

Lees³

1984

Proc. Natl. Acad. Sci. U.S.A.

124

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A model, based on amino acid sequence data, is proposed for the organization of the myelin proteolipid in myelin membrane. The model has three distinctive features: three trans-membrane segments that traverse the lipid bilayer, two cis-membrane domains that enter and exit the same side of the membrane, and a highly charged segment resembling myelin basic protein on the cytoplasmic side of the membrane. It is proposed that the cis-membrane domain(s) can promote the formation and stabilization of the multilamellar myelin structure by hydrophobic interaction with the apposite bilayer across the extracellular space.In the central nervous system, myelin is formed as an extended, modified oligodendroglial plasma membrane that spirals around the axon to form a multilamellar structure (1). During maturation, the membranes become compacted with a close apposition of both the internal and external faces of the membrane. The relative thicknesses of the bilayer, cytoplasmic, and extracellular spaces are 47 A, 30 A, and 30 A, respectively (2,3).Although the myelin sheath is characterized by a relatively high proportion of lipid (70-80%), it is the myelin proteins that provide specificity and perform an important, albeit illdefined role in the maintenance of myelin structure. The predominant proteins are the water-soluble extrinsic myelin basic protein (Mr 18,000), characterized by a high proportion of basic and other polar amino acids (4,5), and the hydrophobic, chloroform/methanol-soluble proteolipid (Mr 30,000) (4, 6). The basic protein is well-characterized (4, 5); however, the proteolipid has resisted structure elucidation, and only recently has its amino acid sequence been determined (7-9). In this article we propose a model ( Fig. 1) for bovine brain myelin proteolipid, based on amino sequence data and analogy with other proteins, and suggest how the proteolipid may help to stabilize the myelin sheath. RESULTS AND DISCUSSIONGeneral Structural Features. The most notable characteristic of the proteolipid sequence (Fig. 2) is the clustering of hydrophobic amino acids into distinct domains. A plot of amino acid hydropathy (11) (Fig. 3) shows four hydrophobic domains of about 30 amino acids each, which alternate with polar segments containing most of the charged and neutral hydrophilic residues. The polar domains also contain all of the predicted ,B-turns (12), suggesting that these regions are extensively folded. These features suggest a model, such as has been proposed for bacteriorhodopsin (13) and other intrinsic membrane proteins (14), wherein the polypeptide chain passes repeatedly through the lipid bilayer, the hydrophobic regions being embedded in the lipid and the polar domains exposed on the external and internal faces of the membrane (Fig. 1). For purposes of discussion, various domains in the proteolipid are defined in terms of polarity, proposed orientation in the membrane, and sequence homology. Thus, Ti (residues 59-90), T2 (residues 151-177) and T3 (residues 238-267) are hydrophobic trans-membrane se...

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Section: Resultsmentioning

confidence: 99%

The structure of bovine brain myelin proteolipid and its organization in myelin.

Laursen¹,

Samiullah²,

Lees³

1984

Proc. Natl. Acad. Sci. U.S.A.

124

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“…Our current findings together with our previous ones (see above) suggest that the minor isoforms recognized specifically by Ab-MBP 215 also become incorporated within the oligodendrocyte membrane itself, and localise to the junction-free compact myelin and to the radial component, where they become enriched relative to the major MBP isoforms. These findings may be illuminated somewhat by considering the secondary structures of the MBP isoforms, as predicted previously (Martenson, 1981(Martenson, , 1986Stoner, 1984Stoner, , 1990. The structures of all four isoforms of MBP show the presence of four antiparallel l~-strands forming a ~-sheet.…”

Section: Differential Immunolabelling Of Radial Component and Junctiomentioning

confidence: 90%

Immunolocalization of 17 and 21.5 kDa MBP isoforms in compact myelin and radial component

Karthigasan

Garvey

Ramamurthy³

et al. 1996

J Neurocytol

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Our previous biochemical analyses revealed that the levels of the minor MBP isoforms 21.5 and 17 kDa are elevated relative to the 14 and 18.5 kDa MBP isoforms in the fraction of isolated myelin of murine CNS that is enriched in interlamellar junctions (or radial component). To substantiate the localization of 21.5 and 17 kDa MBP in the myelin sheath, we used immunoelectron microscopy on thin-sections of mouse optic nerve. Two different polyclonal antibodies were used to distinguish 21.5 and 17 kDa MBP from 14 and 18.5 kDa MBP: Ab-MBP21.5, which was raised against a synthetic peptide corresponding to the exon II amino acid sequence 61-83 of mouse 21.5 kDa MBP (LKQSRSPLPSHARSRPGLCHMYK), and Ab-MBP14, which is immunoreactive to all four isoforms of mouse MBP. Our SDS-PAGE/immunoblotting demonstrated that Ab-MBP21.5, unlike Ab-MBP14, recognized only the 21.5 and 17 kDa MBP isoforms from isolated mouse CNS myelin. Immunolabelling of tissue sections indicated that Ab-MBP14 bound tenfold more to junction-free compact myelin than to radial component, whereas Ab-MBP21.5 bound about equally to the two regions of the myelin sheath. In addition, within the junction-free compact myelin, both antibodies bound nearly three fold more to the major dense line than to the intraperiod line.

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“…We thus could not construct MBP by homology modeling but used instead a piecemeal strategy. We relied strongly on Stoner's (27, 29) and Martenson's (26,28) definitions of the residues forming a ␤-sheet secondary structure.…”

Section: Methodsmentioning

confidence: 99%

Three-dimensional Structure of Myelin Basic Protein

Ridsdale

Beniac

Tompkins

et al. 1997

Journal of Biological Chemistry

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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...

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Prediction of the Secondary Structure of Myelin Basic Protein

Cited by 55 publications

References 76 publications

The structure of bovine brain myelin proteolipid and its organization in myelin.

The structure of bovine brain myelin proteolipid and its organization in myelin.

Immunolocalization of 17 and 21.5 kDa MBP isoforms in compact myelin and radial component

Three-dimensional Structure of Myelin Basic Protein

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