Is myelin basic protein crystallizable?

Sędzik, Jan; Kirschner, Daniel A.

doi:10.1007/bf00966794

Cited by 53 publications

(37 citation statements)

References 80 publications

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“…The nonselective adsorption of MBP to the bilayer surface causes MBP to cover the whole bilayer surface (possibly as a multilayer), forming a gel-like film, as found by viscosity measurements. The gel-like structure of MBP, which possibly is induced by the cohesion between β-sheet regimes of MBP (11,23), may alter the structure and orientation of MBP. The altered structure of MBP might not be optimal for the high interbilayer adhesion force in myelin.…”

Section: Mbp Film Viscosity Between Supported Cytoplasmic Model Myelinmentioning

confidence: 99%

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Lipid domains control myelin basic protein adsorption and membrane interactions between model myelin lipid bilayers

Lee

Banquy

Kristiansen

et al. 2014

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

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The surface forces apparatus and atomic force microscope were used to study the effects of lipid composition and concentrations of myelin basic protein (MBP) on the structure of model lipid bilayers, as well as the interaction forces and adhesion between them. The lipid bilayers had a lipid composition characteristic of the cytoplasmic leaflets of myelin from "normal" (healthy) and "disease-like" [experimental allergic encephalomyelitis (EAE)] animals. They showed significant differences in the adsorption mechanism of MBP. MBP adsorbs on normal bilayers to form a compact film (3-4 nm) with strong intermembrane adhesion (∼0.36 mJ/m 2 ), in contrast to its formation of thicker (7-8 nm) swelled films with weaker intermembrane adhesion (∼0.13 mJ/m 2 ) on EAE bilayers. MBP preferentially adsorbs to liquid-disordered submicron domains within the lipid membranes, attributed to hydrophobic attractions. These results show a direct connection between the lipid composition of membranes and membrane-protein adsorption mechanisms that affects intermembrane spacing and adhesion and has direct implications for demyelinating diseases.lipid raft | biomembrane adhesion | myelin structure | multiple sclerosis | intrinsically unstructured proteins M yelin is an asymmetric multilamellar membrane wrapped around the axons of the central nervous system (CNS) and consists of alternating extracellular and cytoplasmic leaflets (1-3). The bilayer-associated proteins, mainly myelin basic protein (MBP) and proteolipid protein, play an essential role in stabilizing and maintaining the myelin structure. The bilayers are in close contact (∼3 nm separation between lipid headgroupwater interfaces), providing a low dielectric constant through the compact bilayers, which is essential for efficient and fast saltatory propagation of nerve impulses. Any structural changes of the myelin sheath in the CNS, including lesion formation, loss of adhesion, swelling of the water gaps, vacuolization, vesiculation, and complete delamination (demyelination) of the myelin sheath (4-6), are signatures of several inflammatory neurological disorders. These types of disorders are characterized by a broad spectrum of neurological symptoms, such as physical and cognitive disabilities, with multiple sclerosis (MS) being one of the most common demyelinating diseases (2).The primary cause of structural changes in the myelin is still under debate; however, morphological changes of the myelin structure due to diseases such as MS are well known. A wellstudied and accepted animal model for MS is the experimental allergic encephalomyelitis (EAE) of the marmoset (2, 6). Using this model, recent studies conducted with the surface forces apparatus (SFA) have shown that a loss of adhesion force (7) and structural changes of model membranes with lipid composition characteristic of myelin accompanied compositional alterations of the lipid species (8), as well as an electric charge imbalance between lipid molecules and MBP (9). These alterations also change the lateral distribution a...

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Section: Mbp Film Viscosity Between Supported Cytoplasmic Model Myelinmentioning

confidence: 99%

“…MBP is one of the most abundant proteins in the CNS and is an intrinsically unstructured (disordered) protein (11). MBP acts as an intermembrane adhesion protein between the cytoplasmic leaflets of the myelin sheath.…”

mentioning

confidence: 99%

Lipid domains control myelin basic protein adsorption and membrane interactions between model myelin lipid bilayers

Lee

Banquy

Kristiansen

et al. 2014

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

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“…Because of the reluctance of MBP to form crystals (25), its detailed tertiary structure is not known. The main structural models of this protein that exist are from the 1980s and represent abstract syntheses of biochemical data and secondary structure prediction algorithms (Refs.…”

Section: Myelin Basic Protein (Mbp)mentioning

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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“…Efforts to crystallize MBP have so far not been successful. 19 X-ray diffraction and neutron scattering data were collected on MBP-lipid multilayers transferred by the Langmuir-Blodgett technique 20 to solid substrates. Results indicate that MBP does not penetrate beyond the headgroup region and extends approximately 1.5 nm above the membrane surface.…”

Section: Introductionmentioning

confidence: 99%

Adsorption of Membrane-Associated Proteins to Lipid Bilayers Studied with an Atomic Force Microscope: Myelin Basic Protein and Cytochrome c

2000

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Atomic force microscopy was used to study the structure of two membrane-associated proteins adsorbed to various supported phospholipid bilayers in physiological buffer. The aim was (a) to develop a preparation for the investigation of membrane-associated proteins at high resolution under native conditions and (b) to obtain information about the factors that determine the adsorption process and the structure of adsorbed proteins. Therefore, solid-supported membranes were formed on mica by spontaneous vesicle adsorption and spreading. Once a homogeneous, pinhole-free bilayer was formed, solutions containing the proteins at appropriate concentrations were applied. The two positively charged proteins chosen were myelin basic protein (MBP), which plays an essential role in the formation of functional myelin, and cytochrome c. On charged bilayers, MBP applied at concentrations of 0.5-50 µg/mL formed aggregates of defined height (1.9 ( 0.2 nm on negatively and 2.7 ( 0.2 nm on positively charged lipids), which at high concentration covered the entire bilayer. These aggregates are probably monomolecular layers of MBP. On neutral lipid adsorbed MBP formed irregular aggregates. Cytochrome c showed a different adsorption: On negatively charged lipid it formed aggregates of defined, monomolecular height (3.3 ( 0.2 nm). On neutral bilayers small aggregates were observed. On positively charged lipid no adsorption was observed at all. These results indicate that (a) the adsorption of cytomchrome c can be interpreted in terms of a dominating electrostatic interaction; (b) MBP adsorption to lipid bilayers is not exclusively electrostatically driven and depends on the specific lipid bilayer composition; (c) the structure of adsorbed aggregates indicates a strong protein-protein interaction.

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Is myelin basic protein crystallizable?

Cited by 53 publications

References 80 publications

Lipid domains control myelin basic protein adsorption and membrane interactions between model myelin lipid bilayers

Lipid domains control myelin basic protein adsorption and membrane interactions between model myelin lipid bilayers

Three-dimensional Structure of Myelin Basic Protein

Adsorption of Membrane-Associated Proteins to Lipid Bilayers Studied with an Atomic Force Microscope: Myelin Basic Protein and Cytochrome c

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