Myelin Basic Protein, the “Executive” Molecule of the Myelin Membrane

Moscarello, Mario A.

doi:10.1007/978-1-4615-5949-8_2

Cited by 37 publications

(44 citation statements)

References 69 publications

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“…2 is one of the principal constituents of the mammalian myelin sheath and plays a structural role in maintaining myelin stability (1)(2)(3)(4)(5)(6). Immune responses to MBP have been implicated in the pathogenesis of multiple sclerosis (MS), the most common autoimmune disease of the central nervous system in North America and Northern Europe (7,8).…”

Section: Myelin Basic Protein (Mbp)mentioning

confidence: 99%

“…The most abundant isoform in the adult human brain is an 18.5-kDa protein consisting of 170 amino acid residues. It is highly posttranslationally modified, existing in vivo as a series of charge isomers denoted MBP/C1 (least modified, net charge ϩ20) to MBP/C8 (most highly modified, net charge ϩ14 or less) (6,12). Unfractionated MBP isolated from MS patients has been shown to be considerably less cationic than that from normal, agematched controls because of an increase in the proportion of MBP/C8 (13).…”

Section: Myelin Basic Protein (Mbp)mentioning

confidence: 99%

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Characterization of a Recombinant Murine 18.5-kDa Myelin Basic Protein

Bates

Matharu

Ishiyama

et al. 2000

Protein Expression and Purification

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Section: Myelin Basic Protein (Mbp)mentioning

confidence: 99%

Section: Myelin Basic Protein (Mbp)mentioning

confidence: 99%

Characterization of a Recombinant Murine 18.5-kDa Myelin Basic Protein

Bates

Matharu

Ishiyama

et al. 2000

Protein Expression and Purification

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“…It is multifactorial, requiring genetic, environmental (possibly viral), and immunological factors (1). Genetic screens of MS populations have failed to uncover a major susceptibility locus (2), suggesting that MS is a polygenic disease with each gene of small effect.…”

Section: Multiple Sclerosis (Ms)mentioning

confidence: 99%

Multiple Sclerosis

Kim

Mastronardi

Wood

et al. 2003

Molecular & Cellular Proteomics

179

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Myelin basic protein (MBP) represents a candidate autoantigen in multiple sclerosis (MS). We isolated MBP from normal and MS human white matter and purified six components (charge isomers) to compare the post-translational modifications on each. The sites and extent of methylation, deimination, and phosphorylation were documented for all tryptic peptides by mass spectrometry. We found that mono and dimethylated arginine 107 was increased in MS samples; deimination of arginine occurred at a number of sites and was elevated in MS; phosphorylation was observed in 10 peptides in normal samples but was greatly reduced or absent in most peptides from MS samples. Data obtained with MBP isolated from fresh brain obtained from a spontaneously demyelinating mouse model supported the view that the changes observed in human brain were probably related to pathogenesis of demyelination, i.e. we found decreased phosphorylation and decreased amounts of glycogen synthesis kinase in brain homogenates using specific antibodies. This study represents the first to define post-translational modifications in demyelinating disease and suggest an important role in pathogenesis. Molecular & Cellular Proteomics 2:453-462, 2003. Multiple sclerosis (MS)1 is the most common demyelinating disease of the human central nervous system. It is multifactorial, requiring genetic, environmental (possibly viral), and immunological factors (1). Genetic screens of MS populations have failed to uncover a major susceptibility locus (2), suggesting that MS is a polygenic disease with each gene of small effect.Myelin basic protein (MBP), a major myelin protein that accounts for 35% of the total myelin protein, is a strong candidate autoantigen (3). It is a 170-amino acid protein in the human, containing 19 arginyl and 12 lysyl residues, which accounts for its basic character. It is devoid of cysteinyl residues, with a high proportion of disorder promoting amino acids such as A, R, G, Q, S, P, E, and K. It is a member of an expanding group of proteins that include the amyloid and prion proteins, considered to be intrinsically disordered (4), in which the disordered state is the functional state. Because of this, post-translational modifications determine the nature and extent of secondary structure, permitting the protein to adopt multiple conformations for a variety of binding events (5). Because interactions between the positive arginyl and lysyl residues and the negatively charged phosphate groups of the membrane phospholipids are essential to the structure of compact myelin, changes in positive charge of MBP would decrease the strength of these interactions (6).MBP is an unusual protein that has never been crystallized due to the myriad of post-translational modifications it possesses. These include phosphorylation, deamidation, deimination, arginine methylation, and N-terminal acylation. These give rise to a family of microheteromers or "charge isomers," several of which can be resolved by chromatography (7). The effects of some of these modifications o...

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“…3 As a posttranslational modification, it causes conversion of arginine to citrulline through the release of ammonia (deimination/citrullination). Increased citrullination of MBP diminishes its ability to organize lipid bilayers into compact multilayers, creates a more open structure to proteases such as cathepsin D, and thus results in myelin instability.…”

mentioning

confidence: 99%