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PubMed1992

Synthetic peptide specificity of anti-myelin basic protein from multiple sclerosis cerebrospinal fluid.

Human myelin basic protein (h-MBP) purified from central nervous system (CNS) myelin has a molecular mass of 18.5 kDa and 170 residues. Eighteen synthetic peptides ranging from 8 to 25 residues and covering the length of h-MBP were prepared by the Fmoc method. Antibodies to h-MBP (anti-MBP) were isolated and purified from cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) by two-step affinity chromatography. Purified anti-MBP was reacted with increasing amounts of h-MBP as well as each of the 18 synthetic peptides in an initial liquid phase assay, and then titers of free anti-MBP in the resulting mixtures were determined by a solid phase radioimmunoassay. Purified anti-MBP was neutralized by h-MBP and 6 of the 18 synthetic peptides used in this study. The antibody was completely neutralized by peptides No. 12 (residues: 80-97), No. 15 (residues: 91-106) and No. 56 (residues: 75-95) and was partially neutralized by peptides No. 27 (residues: 61-75), No. 16 (residues: 64-78) and No. 21 (residues: 69-83). The 12 remaining synthetic peptides covering both the amino (residues 1-63) and carboxyl (residues 117-162) terminals of h-MBP did not neutralize purified anti-MBP. These results suggest that anti-MBP purified from CSF of patients with MS have affinity for discontinuous epitopes located between residues 61 and 106 on the h-MBP molecule. Alternatively anti-MBP may be polyspecific recognizing different amino acid sequences.

Amino Acid Sequence↗
PubMed2002

Two-dimensional crystal structures of protein kinase C-delta, its regulatory domain, and the enzyme complexed with myelin basic protein.

Two-dimensional crystals of protein kinase C (PKC) delta, its regulatory domain (RDdelta), and the enzyme complexed with the substrate myelin basic protein have been grown on lipid monolayers composed of phosphatidylcholine: phosphatidylserine: diolein (45:50:5, molar ratio). Images have been reconstructed to 10-A resolution. The unit cells of all three proteins have cell edges a = b and interedge angle gamma = 60 degrees. RDdelta has an edge length of 33 +/- 1 A, and its reconstruction is donut shaped. The three-dimensional reconstructions from the PKCdelta C1b crystal structure () can be accommodated in this two-dimensional projection. Intact PKCdelta has an edge length of 46 +/- 1 A in the presence or absence of a nonhydrolyzable ATP analog, AMP-PnP. Its reconstruction has a similar donut shape, which can accommodate the C1b domain, but the spacing between donuts is greater than that in RDdelta; some additional structure is visible between the donuts. The complex of PKCdelta and myelin basic protein, with or without AMP-PnP, has an edge length of 43 +/- 1 A and a distinct structure. These results indicate that the C1 domains of RDdelta are tightly packed in the plane of the membrane in the two-dimensional crystals, that there is a single molecule of PKCdelta in the unit cell, and that its interaction with myelin basic protein induces a shift in conformation and/or packing of the enzyme.

Animals↗
PubMed1999

Diversity of the B cell repertoire to myelin basic protein in rat strains susceptible and resistant to EAE.

Myelin basic protein (MBP) is a major protein of central nervous system myelin which can induce experimental autoimmune encephalomyelitis (EAE) in susceptible laboratory animals. The role of T cells in the induction of EAE has been extensively studied, but the antibody response to MBP has not been well characterized. In the present work, we immunized rats with encephalitogenic guinea-pig MBP and mapped autoreactive antibodies binding to peptides in the rat MBP sequence. We studied the responses of the Lewis rat strain, susceptible to EAE, and the responses of the Fischer and Brown-Norway (BN) rats, resistant to EAE. We found that Lewis rats immunized to guinea-pig MBP develop antibodies to a diversity of MBP epitopes with a dominance of MBP peptide p11-30 and peptides in the 71-140 region. Fischer rats showed a similar pattern of antibody specificities, but with higher titers than the Lewis rats. BN rats, in contrast, developed a very low titer of antibodies and lacked a response to p11-30. Thus, there is no clear correlation between the nature of the anti-MBP antibody response and the state of susceptibility or resistance to EAE induction in the different rat strains.

Amino Acid Sequence↗
PubMed1990

Myelin basic protein stimulates insulin and glucagon secretion from rat pancreatic islets in vitro and in vivo.

The effect of myelin basic protein on insulin and glucagon secretion from rat pancreatic islets was studied in vivo and in vitro. The myelin basic proteins isolated from bovine, human and rat brains all stimulated insulin secretion in a similar fashion. In a static incubation of isolated pancreatic islets, myelin basic protein at doses of 15.6-250 micrograms in a 0.5-ml reaction volume (1.7 X 10(-6) to 2.7 X 10(-5) M) significantly stimulated hormone release. Maximal stimulation, obtained at the 250-micrograms dose, was 6.5-fold greater than control for insulin secretion and 6.7-fold greater than control for glucagon secretion. In the case of glucagon no saturation was observed, but saturation was obvious for insulin release at doses of myelin basic protein of 62.5-250 micrograms, larger doses causing permeabilization of the islet membranes as indicated by leakage of acid phosphatase. At a 100-micrograms dose the time course of insulin secretion induced by myelin basic protein indicated a fast initial release, and after the first 2 h only a little more insulin was released. At the lower doses of myelin basic protein (11 and 33 micrograms) the secretion rate was nearly constant after the first hour. Significant stimulation of glucagon release by myelin basic protein was seen after 60 min, the rate of release being roughly constant at 33- and 100-micrograms doses thereafter. At the 11-micrograms dose significant stimulation of hormone release was observed only after a 4-h incubation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Bovine P2 myelin basic protein crystallizes in three different forms.

P2 protein is a minor component of the myelin membrane. We have crystallized this protein for high-resolution crystallographic study. Three crystal morphologies are available. Two of them are from ammonium sulfate, and one is from polyethyleneglycol (PEG). The unit cell of the most suitable crystals from PEG 4000 has the dimensions a = 91.3 A, b = 99.8 A, c = 56.0 A; is of space group P2(1)2(1)2(1); and contains up to four molecules per asymmetric unit. The limit of resolution is 2.7 A.

Ammonium Sulfate↗
PubMed1990

DNA length polymorphism 5' to the myelin basic protein gene is associated with multiple sclerosis.

A site of DNA polymorphism linked to the myelin basic protein gene, identified as restriction fragment length polymorphism, was analyzed in a population-based study comparing patients with clinically definite multiple sclerosis (MS) and population-matched control subjects. A 0.9-kilobase (kb) genomic DNA fragment (EcoG) encompassing the first exon of the human myelin basic protein gene, located on the long arm of chromosome 18, identified ten alleles arising from a region of DNA, 1.5 kb 5' to the myelin basic protein gene first exon coding region. Produced by RsaI digests and ranging in length from 2.05 to 2.15 kb, these alleles vary in size by up to 100 base pairs due to insertion or deletion, or both, from a 1-kb length of repetitive DNA. Allele frequencies among 65 patients with MS were compared with those of 63 control subjects. Chi square for these data was significant (p less than 0.001), largely due to a preponderance in the patients with MS of alleles in the 2.14- to 2.15-kb range. Comparison of the numbers of patients with MS and control subjects bearing specific alleles showed that 45% of the patients carried at least one allele of 2.14 to 2.15 kb as opposed to 19% of control subjects (p less than 0.005). These data, while preliminary, suggest that patients with MS differ from population-matched control subjects with respect to DNA polymorphism linked to the myelin basic protein gene. Although no pathogenic relationship between this polymorphism and MS can be presupposed, this finding raises the possibility that the myelin basic protein gene or some other myelin basic protein-linked locus may be a factor in susceptibility to MS.

Adult↗
PubMed1983

The effect of the shiverer mutation on myelin basic protein expression in homozygous and heterozygous mouse brain.

We report (a) that the shiverer mutation has pleiotropic phenotypic effects on myelin basic protein expression in the CNS of homozygous (shi/shi) mice and (b) that each of the effects of the shiverer allele is expressed co-dominantly with the wild-type allele in heterozygous (+/shi) animals. First, the total amount of myelin basic protein, as determined by radioimmunoassay, that accumulates in the CNS is approximately 0.1% of the wild-type amount in shi/shi animals and approximately 50% in +/shi animals. Second, the four major forms of myelin basic protein, with molecular weights of 21,500, 18,500, 17,000, and 14,000, that are present in wild-type mouse CNS are undetectable in either whole brain or purified myelin of shi/shi animals, and each of the four proteins is reduced commensurately in brain and myelin of +/shi animals. Third, the small amount of myelin basic protein-related material that does accumulate in the shi/shi brain consists of several polypeptides, with molecular weights ranging from 25,000 to 100,000, the pattern of which is different from that found in wild-type brain. The pattern of myelin basic protein-related polypeptides in +/shi brain is a composite of the wild type and the shiverer mutant. Fourth, messenger RNA from shi/shi brain, when translated in vitro, encodes a set of myelin basic protein-related polypeptides qualitatively similar to that encoded by wild-type messenger RNA, except that the 18,500 and 14,000 translation products are greatly reduced, while other myelin basic protein-related translation products are spared. The pattern of myelin basic protein-related translation products for +/shi messenger RNA is intermediate between the patterns for +/+ and shi/shi messenger RNAs. The results suggest that the genetic lesion in the shiverer mutation impinges on the structural gene (or genes) encoding myelin basic protein or on a cis-acting regulatory element controlling that gene (or genes).

Animals↗
PubMed1978

Cerebrospinal fluid myelin basic protein and multiple sclerosis.

We have previously reported that myelin basic protein appears in CSF during acute attacks of multiple sclerosis. These studies have been extended to over 700 patients, 91 with multiple sclerosis. The data continues to indicate that myelin basic protein is released into cerebrospinal fluid during acute attacks of multiple sclerosis. We are currently characterizing the basic protein in the CSF.

Acute Disease↗
PubMed1980

The binding of myelin basic protein to the Fc region of aggregated IgG and to immune complexes.

Bovine myelin basic protein was found to agglutinate polystyrene particles coated with human polyclonal IgG, monoclonal IgG1, or IgG Fc fragments, but not those coated with IgG F(ab')2 fragments, IgA, or IgM. The agglutination of Fc-coated particles was inhibited by heat-aggregated polyclonal IgG or monoclonal IgG2, IgG3 and IgG4, but not by native IgG. Reduction and alkylation of aggregated IgG did not affect their inhibitory activities. Soluble immune complexes displayed the highest inhibitory activity at a two-fold antigen excess. The interaction between myelin basic protein and aggregated IgG was confirmed by gel exclusion experiments on Sephadex G-200. The possible consequence of these findings could be significant in the interpretation of IgG deposits in brain plaques of multiple sclerosis patients and of the results of immunohistochemical studies, titration of anti-myelin basic protein antibodies and immunoassay of myelin basic protein.

Animals↗
PubMed2000

Kinetic and structural study of the interaction of myelin basic protein with dipalmitoylphosphatidylglycerol layers.

The interaction of myelin basic protein (MBP) with dipalmitoylphosphatidylglycerol films has been investigated by means of a microgravimetric gauge sensitive to the changes in load and structural modifications of the layer deposited onto its surface. Fourier transform infrared spectroscopy, circular dichroism, and x-ray diffraction have confirmed protein uptake by the lipid phase along with a global disordering effect onto the lipid alkyl chains and have shown a temporal evolution of the structure of water penetrating the lipid phase together with the protein. These effects are clearly related to the temporal variation of the microgravimetric gauge signal. Finally, measurements carried out on pre-annealed samples point out the role of mesoscopic morphology in determining the pathways through which MBP penetrates the lipid multilayer. The results obtained in our model system could be useful in clarifying the mechanisms of the myelinating and demyelinating processes that take place in the natural membrane.

Animals↗
PubMed1975

Decreased myelin basic protein content of the aged human brain.

Myelin basic protein was extracted from frontal lobe white matter obtained at autopsy from seven individuals ranging in age from 72 to 78 years. Qualitative and quantitative comparisons were made between basic protein from this group and that extracted from another group of individuals ranging in age from 45 to 65 years. The basic protein content of the older brains was considerably lower than that of the younger brains. Qualitative studies that included assay for encephalitogenic activity, disk gel electrophoresis at pH 4.3, and immunoprecipitation did not reveal any difference in the basic protein derived from the two age groups. Possible factors that may help explain the decreased basic protein content of the aged brain are discussed.

Aged↗
PubMed1990

Interactions between bovine myelin basic protein and zwitterionic lysophospholipids.

The binding of myelin basic protein to lysolauroylphosphatidylcholine (lysoLPC) and lysolauroylphosphatidylethanolamine was investigated at neutral pH using gel partition chromatography and equilibrium dialysis at 20 and 37 degrees C. The results show that the protein-lysolipid interactions are highly cooperative and that the free lysolipid concentration at which the binding commences is markedly influenced by both the chemical structure of the lysolipids and the temperature. The binding begins just below the critical micelle concentration for both lysolipids, which suggests that the forces governing micellization and the binding are similar. Circular dichroism (CD) spectroscopy was used to follow changes in the conformation of the protein caused by lysomyristoylphosphatidylcholine and lysoLPC. The CD results indicate that lysolipid association with the protein commences below the critical micelle concentration and continues above this concentration. Mechanisms for the lysolipid-protein interaction, which are consistent with the binding and CD data, are discussed.

Animals↗
PubMed2001

[Preliminary study of the facial nerve regeneration in the chamber: the influence of myelin basic protein].

OBJECTIVE: To study the role of exogenous myelin basic protein(MBP) in neural repairment. METHODS: Adult New Zealand rabbits were employed in vivo preparation. A 12 microL nerve growth chamber was created by suturing the proximal and distal stumps of a transected facial never (FN) trunk into a tube. The regenerated nerves within the chambers were dissected and fixed for histological studies with light microscope at 4, 6 and 8 weeks respectively following the surgery. RESULTS: Morphological analysis of nerves showed no difference between the MBP and control group in the size of the regeneration FN within the chambers, diameters of myelinated axons, thickness of myelin sheath and number of myelin axons grew into the distal end of chamber at 4 weeks. At 6 and 8 weeks after operation, the MBP group showed a more mature-appearance regenerative nerve comparing to control group. Especially, the enhancement of maturation in the regeneration axons was very noticeable at 6 weeks. CONCLUSION: The study showed that pharmacological administration of exogenous MBP within a chamber at the time of entubational nerve repair enhances regeneration of myelinated axons across the sectioned ends of FN.

Animals↗
PubMed1986

Rat and mouse monoclonal antibodies to human myelin basic protein.

BALB/c mice and Lewis rats were immunized with human myelin basic protein and its N- and C-terminal fragments. Mouse X mouse fusions produced seven monoclonal antibodies, all of the IgG class and directed against the N-terminal fragment. Five of the antibodies seemed to be against the same epitope, between amino acid residues 92 and 118. One antibody bound between residues 45 and 91, and the remaining antibody reacted with both peptides 1-44 and 45-91. Three monoclonal antibodies, all of the IgM class, were obtained by rat X rat hybridization. Two monoclonal antibodies, raised against whole myelin basic protein and the C-terminal fragment, respectively, each bound to peptide 118-178. The remaining antibody, raised against the N-terminal fragment, bound to peptide 45-91. These monoclonal antibodies are of interest for use in clinical radioimmunoassays and for immunohistochemical investigation of the structural relationships of the myelin sheath.

Animals↗
PubMed1993

The T-lymphocyte response against myelin-associated glycoprotein and myelin basic protein in patients with multiple sclerosis.

In addition to myelin basic protein (MBP), other minor components of myelin, such as myelin-associated glycoprotein (MAG), may be important autoantigens in MS. To determine whether MAG might be involved in an autoimmune reaction in MS, we screened peripheral blood lymphocytes from MS patients and normal subjects for their sensitization to human MBP and MAG antigen using a [3H]thymidine incorporation assay. We recorded three patterns in MS patients: (1) patients who responded neither to MAG nor to MBP (4/11); (2) patients who responded to both MBP and MAG (5/11); and (3) patients who gave an exclusive response to MAG (2/11). The 10 healthy controls did not respond to either MAG or MBP. That some individuals with MS expressed a specific response against MAG and that more than 50% of MS patients expressed a sensitization to MAG suggest that MAG may have a role in the pathogenesis of MS.

Adult↗
PubMed1991

Carboxylmethylation affects the proteolysis of myelin basic protein by Staphylococcus aureus V8 proteinase.

Bovine myelin basic protein (MBP), charge isoform 1 (C1) was carboxylmethylated by the enzyme D-aspartyl/L-isoaspartyl protein methyltransferase (EC. 2.1.1.77) and the carboxylmethylated protein was subjected to proteolysis by sequencing grade staphylococcal V8 proteinase at pH 4.0 to identify its carboxylmethylated modified aspartate and/or asparagine residues which are recognized by this methyltransferase. Native MBP, C1 was treated similarly and the proteolysis products were compared, using electrophoretic, chromatographic and amino acid sequencing techniques. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) revealed differences in the kinetics of proteolysis between the native and the carboxylmethylated MBP, C1 which were confirmed using HPLC. Partial sequencing of the native and carboxylmethylated fragments eluting at about 29 min (P29) revealed cleavage of native MBP, C1 at Gly-127-Gly-128 and of the carboxylmethylated MBP, C1 at Phe-124-Gly-125. Additional evidence including tryptic subdigestion of carboxylmethylated P29 disclosed the following partial sequence for this peptide: Gly-Tyr-Gly-Gly-Arg-Ala-Ser-Asp-Tyr-Lys-Ser-Ala-His-Lys-Gly-Leu-Lys- Gly-His-Asp-Ala-Gln-Gly-Thr-Leu-Ser-Lys-Ileu-Phe-Lys-. This sequence matches MBP residues 125-154. As a result of these findings, Asp-132 and Asp-144 were identified as two of the modified (isomerized or racemized) methyl-accepting L-aspartates in MBP. The results of the proteolysis experiments wherein the sequencing grade staphylococcal V8 proteinase was used at the rarely tested pH of 4.0, rather than at its commonly tested pH of 7.8, also disclose that the proteinase totally failed to recognize and hence cleave the two Glu-X bonds (Glu-82-Asn-83 and Glu-118-Gly-119) of MBP, preferring to cleave the protein at a number of hitherto unreported sites.

Amino Acid Sequence↗
PubMed2003

Myelin basic protein has multiple calmodulin-binding sites.

Myelin basic protein (MBP) has been shown to bind calmodulin (CaM) in a specific Ca(2+)-dependent manner via a primary target sequence at its C-terminus [Protein Sci. 12 (2003) 1507]. Upon deimination of MBP, the nature of the interaction changed significantly, suggesting either a new binding site or different conformers with different affinities for CaM. In order to resolve this issue, we investigated here the CaM-binding properties of N- and C-terminal deletion mutants of MBP using Trp fluorescence spectroscopy and mass spectrometry. We conclude that there is an additional CaM-binding site on MBP in a central segment (we posit murine residues 82-93) that forms an amphipathic alpha-helix.

Amino Acid Sequence↗