Myelin basic protein
|Myelin basic protein|
Rendering of MBP from PDB
|RNA expression pattern|
Myelin basic protein (MBP) is a protein believed to be important in the process of myelination of nerves in the nervous system. The myelin sheath is a multi-layered membrane, unique to the nervous system, that functions as an insulator to greatly increase the velocity of axonal impulse conduction. MBP maintains the correct structure of myelin, interacting with the lipids in the myelin membrane.
MBP was initially sequenced in 1971 after isolation from myelin membranes. Since that time, knockout mice deficient in MBP that showed decreased amounts of CNS myelination and a progressive disorder characterized by tremors, seizures, and early death have been developed. The human gene for MBP is on chromosome 18; the protein localizes to the CNS and to various cells of the hematopoietic system.
The pool of MBP in the central nervous system is very diverse, with several splice variants being expressed and a large number of post-translational modifications on the protein, which include phosphorylation, methylation, deamidation, and citrullination. These forms differ by the presence or the absence of short (10 to 20 residues) peptides in various internal locations in the sequence. In general, the major form of MBP is a protein of about 18.5 Kd (170 residues).
The protein encoded by the classic MBP gene is a major constituent of the myelin sheath of oligodendrocytes and Schwann cells in the nervous system. However, MBP-related transcripts are also present in the bone marrow and the immune system. These mRNAs arise from the long MBP gene (otherwise called "Golli-MBP") that contains 3 additional exons located upstream of the classic MBP exons. Alternative splicing from the Golli and the MBP transcription start sites gives rise to 2 sets of MBP-related transcripts and gene products. The Golli mRNAs contain 3 exons unique to Golli-MBP, spliced in-frame to 1 or more MBP exons. They encode hybrid proteins that have N-terminal Golli aa sequence linked to MBP aa sequence. The second family of transcripts contain only MBP exons and produce 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.
Role in disease
Interest in MBP has centered on its role in demyelinating diseases, in particular, multiple sclerosis (MS). Several studies have shown a role for antibodies against MBP in the pathogenesis of MS. Some studies have linked a genetic predisposition to MS to the MBP gene, though a majority have not.
A targeted immune response to MBP has been researched in lethal rabies 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%.
A "molecular mimicry" hypothesis of multiple sclerosis has been suggested, in which T cells are, in essence, confusing MBP with human herpesvirus-6. Researchers in the United States created a synthetic peptide with a sequence identical to that of an HHV-6 peptide. They were 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.
Myelin basic protein has been shown to interact in vivo with Proteolipid protein 1, and in vitro with Calmodulin, Actin, Tropomyosin, Tubulin, Clathrin, 2',3'-Cyclic-nucleotide 3'-phosphodiesterase and multiple molecules of the Immune system.
- Sakamoto Y, Kitamura K, Yoshimura K, Nishijima T, Uyemura K (March 1987). "Complete amino acid sequence of PO protein in bovine peripheral nerve myelin". J. Biol. Chem. 262 (9): 4208–14. PMID 2435734.
- Deber CM, Reynolds SJ (April 1991). "Central nervous system myelin: structure, function, and pathology". Clin. Biochem. 24 (2): 113–34. doi:10.1016/0009-9120(91)90421-a. PMID 1710177.
- Inouye H, Kirschner DA (January 1991). "Folding and function of the myelin proteins from primary sequence data". J. Neurosci. Res. 28 (1): 1–17. doi:10.1002/jnr.490280102. PMID 1710279.
- Eylar EH, Brostoff S, Hashim G, Caccam J, Burnett P (September 1971). "Basic A1 protein of the myelin membrane. The complete amino acid sequence". J. Biol. Chem. 246 (18): 5770–84. PMID 5096093.
- 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". Cytogenet. Cell Genet. 39 (4): 246–9. doi:10.1159/000132152. PMID 2414074.
- Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (December 2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell Melanoma Res 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.
- "Entrez Gene: myelin basic protein".
- Berger T, Rubner P, Schautzer F, Egg R, Ulmer H, Mayringer I, Dilitz E, Deisenhammer F, Reindl M (July 2003). "Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event". N. Engl. J. Med. 349 (2): 139–45. doi:10.1056/NEJMoa022328. PMID 12853586.
- Roy A, Hooper DC (August 2007). "Lethal silver-haired bat rabies virus infection can be prevented by opening the blood–brain barrier". J. Virol. 81 (15): 7993–8. doi:10.1128/JVI.00710-07. PMC 1951307. PMID 17507463.
- Tejada-Simon, Maria (2003). "Cross-reactivity with myelin basic protein and human herpesvirus-6 in multiple sclerosi". annals of neurology 53 (2): 189–97. doi:10.1002/ana.10425. PMID 12557285.
- Wood DD, Vella GJ, Moscarello MA (October 1984). "Interaction between human myelin basic protein and lipophilin". Neurochem. Res. 9 (10): 1523–31. doi:10.1007/BF00964678. PMID 6083474.
- Edwards AM, Ross NW, Ulmer JB, Braun PE (January 1989). "Interaction of myelin basic protein and proteolipid protein". J. Neurosci. Res. 22 (1): 97–102. doi:10.1002/jnr.490220113. PMID 2467009.
- Harauz, George et al. (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.
- Boylan KB, Ayres TM, Popko B et al. (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. PMID 1689270.
- Kishimoto A, Nishiyama K, Nakanishi H et al. (1985). "Studies on the phosphorylation of myelin basic protein by protein kinase C and adenosine 3':5'-monophosphate-dependent protein kinase.". J. Biol. Chem. 260 (23): 12492–9. PMID 2413024.
- 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.". Cytogenet. Cell Genet. 39 (4): 246–9. doi:10.1159/000132152. PMID 2414074.
- Kamholz J, de Ferra F, Puckett C, Lazzarini R (1986). "Identification of three forms of human myelin basic protein by cDNA cloning.". Proc. Natl. Acad. Sci. U.S.A. 83 (13): 4962–6. doi:10.1073/pnas.83.13.4962. PMC 323864. PMID 2425357.
- Scoble HA, Whitaker JN, Biemann K (1986). "Analysis of the primary sequence of human myelin basic protein peptides 1-44 and 90-170 by fast atom bombardment mass spectrometry.". J. Neurochem. 47 (2): 614–6. doi:10.1111/j.1471-4159.1986.tb04544.x. PMID 2426402.
- Roth HJ, Kronquist K, Pretorius PJ et al. (1986). "Isolation and characterization of a cDNA coding for a novel human 17.3K myelin basic protein (MBP) variant.". J. Neurosci. Res. 16 (1): 227–38. doi:10.1002/jnr.490160120. PMID 2427738.
- Popko B, Puckett C, Lai E et al. (1987). "Myelin deficient mice: expression of myelin basic protein and generation of mice with varying levels of myelin.". Cell 48 (4): 713–21. doi:10.1016/0092-8674(87)90249-2. PMID 2434243.
- Kamholz J, Spielman R, Gogolin K et al. (1987). "The human myelin-basic-protein gene: chromosomal localization and RFLP analysis.". Am. J. Hum. Genet. 40 (4): 365–73. PMC 1684086. PMID 2437795.
- Roth HJ, Kronquist KE, Kerlero de Rosbo N et al. (1987). "Evidence for the expression of four myelin basic protein variants in the developing human spinal cord through cDNA cloning.". J. Neurosci. Res. 17 (4): 321–8. doi:10.1002/jnr.490170402. PMID 2442403.
- Shoji S, Ohnishi J, Funakoshi T et al. (1988). "Phosphorylation sites of bovine brain myelin basic protein phosphorylated with Ca2+-calmodulin-dependent protein kinase from rat brain.". J. Biochem. 102 (5): 1113–20. PMID 2449425.
- Wood DD, Moscarello MA (1989). "The isolation, characterization, and lipid-aggregating properties of a citrulline containing myelin basic protein.". J. Biol. Chem. 264 (9): 5121–7. PMID 2466844.
- Edwards AM, Ross NW, Ulmer JB, Braun PE (1989). "Interaction of myelin basic protein and proteolipid protein.". J. Neurosci. Res. 22 (1): 97–102. doi:10.1002/jnr.490220113. PMID 2467009.
- Streicher R, Stoffel W (1989). "The organization of the human myelin basic protein gene. Comparison with the mouse gene.". Biol. Chem. Hoppe-Seyler 370 (5): 503–10. doi:10.1515/bchm3.1989.370.1.503. PMID 2472816.
- Lennon VA, Wilks AV, Carnegie PR (1971). "Immunologic properties of the main encephalitogenic peptide from the basic protein of human myelin.". J. Immunol. 105 (5): 1223–30. PMID 4099924.
- Carnegie PR (1972). "Amino acid sequence of the encephalitogenic basic protein from human myelin.". Biochem. J. 123 (1): 57–67. PMC 1176899. PMID 4108501.
- Baldwin GS, Carnegie PR (1971). "Specific enzymic methylation of an arginine in the experimental allergic encephalomyelitis protein from human myelin.". Science 171 (3971): 579–81. doi:10.1126/science.171.3971.579. PMID 4924231.
- Baldwin GS, Carnegie PR (1972). "Isolation and partial characterization of methylated arginines from the encephalitogenic basic protein of myelin.". Biochem. J. 123 (1): 69–74. PMC 1176900. PMID 5128665.
- Wood DD, Vella GJ, Moscarello MA (1985). "Interaction between human myelin basic protein and lipophilin.". Neurochem. Res. 9 (10): 1523–31. doi:10.1007/BF00964678. PMID 6083474.
- Gibson BW, Gilliom RD, Whitaker JN, Biemann K (1984). "Amino acid sequence of human myelin basic protein peptide 45-89 as determined by mass spectrometry.". J. Biol. Chem. 259 (8): 5028–31. PMID 6201481.
- Pribyl TM, Campagnoni CW, Kampf K et al. (1993). "The human myelin basic protein gene is included within a 179-kilobase transcription unit: expression in the immune and central nervous systems.". Proc. Natl. Acad. Sci. U.S.A. 90 (22): 10695–9. doi:10.1073/pnas.90.22.10695. PMC 47844. PMID 7504278.
- Shanshiashvili L, Mikeladze D (2003). "Some aspects of myelin basic protein.". J. Biol. Phys. Chem. 3: 96–9. doi:10.4024/18SH03R.jbpc.03.03.