Myelin basic protein (MBP) is aprotein important in the process ofmyelination ofnerves in thenervous system. Themyelin sheath is a multi-layered membrane, unique to the nervous system, that functions as an insulator to greatly increase the velocity ofaxonal impulse conduction.[5] MBP maintains the correct structure of myelin, interacting with thelipids in the myelin membrane.[6][7]
MBP was initiallysequenced in 1971 after isolation from bovine myelinmembranes.[8] MBPknockout mice calledshiverer mice were subsequently developed and characterized in the early 1980s.Shiverer mice exhibit decreased amounts of CNS myelination and a progressive disorder characterized bytremors,seizures, and early death. The humangene for MBP is onchromosome 18;[9] the protein localizes to the CNS and to variouscells of thehematopoietic lineage.
The protein encoded by the classicMBP gene is a major constituent of themyelin sheath ofoligodendrocytes andSchwann cells in the nervous system. However, MBP-related transcripts are also present in the bone marrow and the immune system. ThesemRNAs arise from the longMBP gene (otherwise called "Golli-MBP") that contains three additional exons located upstream of the classic MBP exons.Alternative splicing from the Golli and the MBP transcription start sites gives rise to two sets of MBP-related transcripts and gene products. The Golli mRNAs contain three exons unique to Golli-MBP, spliced in-frame to one or more MBP exons. They encode hybrid proteins that have anN-terminal Golli amino acid sequence linked to the MBP amino acid sequence. The second family of transcripts contains only MBP exons and produces the well-characterized myelin basic proteins. This complex gene structure is conserved among species, suggesting that the MBP transcription unit is an integral part of the Golli transcription unit and that this arrangement is important for the function and/or regulation of these genes.[11] At protein level, the concentration of MBP in theCNS is tenfold higher in sections ofwhite matter compared withcerebral cortex.[12]
Myelin basic protein has been classified as anintrinsically disordered protein that has no stable secondary structure in solution.[13] Like most IDPs, it has a high net charge and a low mean hydrophobicity, minimizing the hydrophobic effect that drives traditional protein folding. It does contain some exceptions to normal IDP amino acid content. For example, MBP has more arginine and less glutamic acid than most IDPs. However, this is likely because those changes are necessary for MBP to be sufficiently basic and positively charged to correctly interact with the membrane.[14] Notably, MBP has been shown to adopt a more stable secondary structure on interaction with lipids.[15][16]NMR and Cys-specific spin labeling experiments have predicted this structure to contain beta sheet and regions ofamphipathic helix.[17]
As implied by its name, myelin basic protein is significantly basic, with anisoelectric point of 10. It is thought to associate with the cell membrane through electrostatic interactions between its positive charges and negatively charged phospholipid heads of the plasma membrane.[18] It can undergo a large variety of post-translational modifications, creating various charge isomers known as C1-C6 or C8.[19] These modifications includephosphorylation,methylation,deamidation,citrullination,ADP-ribosylation, and N-terminalacylation . C1 is the least modified, while C8 is the most distinct, containing 6-11 additional citrullinations. Since each of these decreases its positive charge, C8 has the smallest net positive charge of the isomers. Alternations in these post-translational modifications have been associated withdemyelinating diseases. Notably, MBP isolated from individuals withmultiple sclerosis have had a higher degree of citrullination and a smaller positive charge. In a rare, severe form of MS known as Marburg's syndrome, the citrullination was even more extensive.[18]
Interest in MBP has centered on its role indemyelinating diseases, in particular,multiple sclerosis (MS). The target antigen of the autoimmune response in MS has not yet been identified. However, several studies have shown a role forantibodies against MBP in thepathogenesis of MS.[20] Some studies have linked agenetic predisposition to MS to the MBP gene, though a majority have not.
A "molecular mimicry" hypothesis of multiple sclerosis has been suggested, in whichT cells are, in essence, confusing MBP withhuman herpesvirus-6. Researchers in the United States created a synthetic peptide with a sequence identical to that of an HHV-6 peptide. Elevated levels of MBP have been found in the cerebrospinal fluid of patients withHIV infections and signs of encephalopathy, and although MBP does not seem to be a sensitive diagnostic marker of HIV encephalopathy, it has been suggested that it may serve a role as a prognostic indicator of disease progression.[21] It is able to show that T cells were activated by this peptide. These activated T cells also recognized and initiated an immune response against a synthetically created peptide sequence that is identical to part of human MBP. During their research, they found that the levels of these cross-reactive T cells are significantly elevated in multiple sclerosis patients.[22]
Some research has shown that inoculating an animal with MBP to generate an MBP-specific immune response against it increasesblood–brain barrier permeability. Permeability is enhanced when the animal is inoculated against non-specific proteins.[23]
A targeted immune response to MBP has been implicated in lethalrabies infection. The inoculation of MBP generates increases the permeability of the blood–brain barrier (BBB), allowing immune cells to enter the brain, the primary site of rabies virus replication. In a study of mice infected with Silver-haired bat rabies virus (SHBRV), the mortality rate of mice treated with MBP improved 20%-30% over the untreated control group. It is significant to note that healthy uninfected mice treated with MBP showed an increase in mortality rate between 0% and 40%.[24]
^Inouye H, Kirschner DA (January 1991). "Folding and function of the myelin proteins from primary sequence data".Journal of Neuroscience Research.28 (1):1–17.doi:10.1002/jnr.490280102.PMID1710279.S2CID8598890.
^Saxe DF, Takahashi N, Hood L, Simon MI (1985). "Localization of the human myelin basic protein gene (MBP) to region 18q22----qter by in situ hybridization".Cytogenetics and Cell Genetics.39 (4):246–249.doi:10.1159/000132152.PMID2414074.
^Anderson TR, Slotkin TA (August 1975). "Maturation of the adrenal medulla--IV. Effects of morphine".Biochemical Pharmacology.24 (16):1469–1474.doi:10.1016/0006-2952(75)90020-9.PMID7.
^Harauz G, Ishiyama N, Hill CM, Bates IR, Libich DS, Farès C (May 2004). "Myelin basic protein-diverse conformational states of an intrinsically unstructured protein and its roles in myelin assembly and multiple sclerosis".Micron.35 (7):503–542.doi:10.1016/s0968-4328(04)00096-4.PMID15219899.
^Moroi K, Sato T (August 1975). "Comparison between procaine and isocarboxazid metabolism in vitro by a liver microsomal amidase-esterase".Biochemical Pharmacology.24 (16):1517–1521.doi:10.1016/0006-2952(75)90029-5.PMID8.
^Marniemi J, Parkki MG (September 1975). "Radiochemical assay of glutathione S-epoxide transferase and its enhancement by phenobarbital in rat liver in vivo".Biochemical Pharmacology.24 (17):1569–1572.doi:10.1016/0006-2952(75)90080-5.PMID9.
^Zand R, Li MX, Jin X, Lubman D (February 1998). "Determination of the sites of posttranslational modifications in the charge isomers of bovine myelin basic protein by capillary electrophoresis-mass spectroscopy".Biochemistry.37 (8):2441–2449.doi:10.1021/bi972347t.PMID9485392.
^Tejada-Simon MV, Zang YC, Hong J, Rivera VM, Zhang JZ (February 2003). "Cross-reactivity with myelin basic protein and human herpesvirus-6 in multiple sclerosis".Annals of Neurology.53 (2):189–197.doi:10.1002/ana.10425.PMID12557285.S2CID43317994.
^Namer IJ, Steibel J, Poulet P, Armspach JP, Mohr M, Mauss Y, Chambron J (February 1993). "Blood-brain barrier breakdown in MBP-specific T cell induced experimental allergic encephalomyelitis. A quantitative in vivo MRI study".Brain. 116 ( Pt 1) (1):147–159.doi:10.1093/brain/116.1.147.PMID7680933.
^Wood DD, Vella GJ, Moscarello MA (October 1984). "Interaction between human myelin basic protein and lipophilin".Neurochemical Research.9 (10):1523–1531.doi:10.1007/BF00964678.PMID6083474.S2CID9751765.
^Edwards AM, Ross NW, Ulmer JB, Braun PE (January 1989). "Interaction of myelin basic protein and proteolipid protein".Journal of Neuroscience Research.22 (1):97–102.doi:10.1002/jnr.490220113.PMID2467009.S2CID33666906.
^Harauz G, Ishiyama N, Hill CM, Bates IR, Libich DS, Farès C (2004). "Myelin basic protein-diverse conformational states of an intrinsically unstructured protein and its roles in myelin assembly and multiple sclerosis".Micron.35 (7):503–542.doi:10.1016/j.micron.2004.04.005.PMID15219899.
Boylan KB, Ayres TM, Popko B, Takahashi N, Hood LE, Prusiner SB (January 1990). "Repetitive DNA (TGGA)n 5' to the human myelin basic protein gene: a new form of oligonucleotide repetitive sequence showing length polymorphism".Genomics.6 (1):16–22.doi:10.1016/0888-7543(90)90443-X.PMID1689270.
Saxe DF, Takahashi N, Hood L, Simon MI (1985). "Localization of the human myelin basic protein gene (MBP) to region 18q22----qter by in situ hybridization".Cytogenetics and Cell Genetics.39 (4):246–249.doi:10.1159/000132152.PMID2414074.
Scoble HA, Whitaker JN, Biemann K (August 1986). "Analysis of the primary sequence of human myelin basic protein peptides 1-44 and 90-170 by fast atom bombardment mass spectrometry".Journal of Neurochemistry.47 (2):614–616.doi:10.1111/j.1471-4159.1986.tb04544.x.PMID2426402.S2CID22531833.
Roth HJ, Kronquist K, Pretorius PJ, Crandall BF, Campagnoni AT (1986). "Isolation and characterization of a cDNA coding for a novel human 17.3K myelin basic protein (MBP) variant".Journal of Neuroscience Research.16 (1):227–238.doi:10.1002/jnr.490160120.PMID2427738.S2CID38277667.
Popko B, Puckett C, Lai E, Shine HD, Readhead C, Takahashi N, et al. (February 1987). "Myelin deficient mice: expression of myelin basic protein and generation of mice with varying levels of myelin".Cell.48 (4):713–721.doi:10.1016/0092-8674(87)90249-2.PMID2434243.S2CID25224473.
Roth HJ, Kronquist KE, Kerlero de Rosbo N, Crandall BF, Campagnoni AT (1987). "Evidence for the expression of four myelin basic protein variants in the developing human spinal cord through cDNA cloning".Journal of Neuroscience Research.17 (4):321–328.doi:10.1002/jnr.490170402.PMID2442403.S2CID37138877.
Edwards AM, Ross NW, Ulmer JB, Braun PE (January 1989). "Interaction of myelin basic protein and proteolipid protein".Journal of Neuroscience Research.22 (1):97–102.doi:10.1002/jnr.490220113.PMID2467009.S2CID33666906.
Streicher R, Stoffel W (May 1989). "The organization of the human myelin basic protein gene. Comparison with the mouse gene".Biological Chemistry Hoppe-Seyler.370 (5):503–510.doi:10.1515/bchm3.1989.370.1.503.PMID2472816.
Wood DD, Vella GJ, Moscarello MA (October 1984). "Interaction between human myelin basic protein and lipophilin".Neurochemical Research.9 (10):1523–1531.doi:10.1007/BF00964678.PMID6083474.S2CID9751765.
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