Multilamellar packing of myelin modeled by lipid-bound MBP

Riccio, P.; Fasano, A.; Borenshtein, N.; Bleve-Zacheo, T.; Kirschner, Daniel A.

doi:10.1002/(sici)1097-4547(20000215)59:4<513::aid-jnr6>3.0.co;2-m

Cited by 35 publications

(24 citation statements)

References 46 publications

(62 reference statements)

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“…1, c and d). The aggregation state induced by MBP is a good paradigm for the in vivo situation, because the addition of MBP to lipid vesicles can reform the lipid into stable multilamellar structures similar to the myelin sheath (3,28).…”

Section: Resultssupporting

confidence: 92%

An Immunodominant Epitope of Myelin Basic Protein Is an Amphipathic α-Helix

Bates

Feix

Boggs

et al. 2004

Journal of Biological Chemistry

124

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Myelin basic protein is a candidate autoantigen in multiple sclerosis. One of its dominant antigenic epitopes is segment Pro 85 to Pro 96 (human sequence numbering, corresponding to Pro 82 to Pro 93 in the mouse). There have been several, contradictory predictions of secondary structure in this region; either ␤-sheet, ␣-helix, random coil, or combinations thereof have all been proposed. In this paper, molecular dynamics and site-directed spin labeling in aqueous solution indicate that this segment forms a transient ␣-helix, which is stabilized in 30% trifluoroethanol. When bound to a myelin-like membrane surface, this antigenic segment exhibits a depth profile that is characteristic of an amphipathic ␣-helix, penetrating up to 12 Å into the bilayer. The ␣-helix is tilted ϳ9°, and the central lysine is in an ideal snorkeling position for side-chain interaction with the negatively charged phospholipid head groups.Multiple sclerosis (MS) 1 is thought to be an autoimmune disease characterized by chronic inflammatory response against myelin in the central nervous system. There is significant evidence that myelin basic protein (MBP) is a candidate antigen for T-cells and autoantibodies in MS (1). The 18.5-kDa isoform of MBP maintains the compaction of the myelin sheath in the central nervous system by anchoring the cytoplasmic face of the two apposing bilayers (2, 3). The mechanism and sites that are important for membrane adhesion are not known.The level of anti-MBP antibodies is increased in the cerebrospinal fluid of patients with active MS (4), as well as in 96% of patients with relapsing and chronic MS (5). An MBP region between Pro 85 and Pro 96 (human sequence numbering) was identified to be a minimal B cell epitope and a T cell epitope for HLA DR2b (DRB1*1501)-restricted T cells that recognize the protein (1, 6). This epitope overlaps with the DR2a-restricted epitope for T-cells reactive to MBP residues 87-106 (7). Experimental treatments for MS based on peptide mimetics of MBP have focused on this region of the protein (8).In solution, MBP is "intrinsically unstructured" (or "natively unfolded") (9). Upon binding to detergents or lipids, the levels of ␤-sheet and especially ␣-helical structure increase dramatically (10, 11). Presently the tertiary structure of MBP is unknown, with the most detailed predictions coming from Martenson (12) and Stoner (13) in the mid-1980s. In these models, as well as in a newer model based upon further research on an electron microscopy single-particle reconstruction, residues 86 -92 are found in a ␤-sheet (14, 15). Using [ 1 H]NMR and circular dichroic spectropolarimetry of various MBP peptides with detergent micelles, Mendz et al. (16) suggested that there were discrete interaction sites in the protein, one of which could be a helix between residues 87 and 97. Based on the arrangement of hydrophobic and hydrophilic residues, Warren et al. (6) predicted that this epitope of MBP was an amphipathic ␣-helix located at the interface between the oligodendrocyte cytoplasm and the me...

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Section: Resultssupporting

confidence: 92%

An Immunodominant Epitope of Myelin Basic Protein Is an Amphipathic α-Helix

Bates

Feix

Boggs

et al. 2004

Journal of Biological Chemistry

124

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“…This swelling can be attributed to the charge neutralization, followed by charge overcompensation, which is also common in the flocculation of colloidal particles by polyelectrolytes (30). Excess negative charge causes electrostatic swelling, but excess positive charge, i.e., excess MBP, causes swelling through the formation of a weak gel of MBP (26), possibly with some lipid (11,26,31) that forces the bilayers apart. ¶ This gel exhibits a phase transition on being compressed, which allows it to be collapsed when subjected to a compressive pressure of Ϸ1 MPa (10 atm).…”

Section: Table 1 Lipid Compositions Of Healthy and Diseased Bilayersmentioning

confidence: 39%

“…It has been shown in previous work that in experimental allergic encephalomyelitis (EAE) in the common marmoset-an established animal model for MS (10)-the lipid composition changes, in particular the ratios of charged to uncharged lipids (Table 1). In other studies, both the charged lipid and MBP isomer composition and the balance (relative amounts) between the charged lipid and MBP isomer composition change in MS and EAE tissues (11,12). We show here that either an excess or a deficit of MBP relative to anionic lipids affects the interactions between myelin membranes across the cytoplasmic space, although we note that whether swelling and demyelination occur at both the extracellular and cytoplasmic spaces during MS has not yet been established.…”

mentioning

confidence: 94%

Interaction forces and adhesion of supported myelin lipid bilayers modulated by myelin basic protein

Min

Kristiansen

Boggs

et al. 2009

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

150

163

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Force-distance measurements between supported lipid bilayers mimicking the cytoplasmic surface of myelin at various surface coverages of myelin basic protein (MBP) indicate that maximum adhesion and minimum cytoplasmic spacing occur when each negative lipid in the membrane can bind to a positive arginine or lysine group on MBP. At the optimal lipid/protein ratio, additional attractive forces are provided by hydrophobic, van der Waals, and weak dipolar interactions between zwitterionic groups on the lipids and MBP. When MBP is depleted, the adhesion decreases and the cytoplasmic space swells; when MBP is in excess, the bilayers swell even more. Excess MBP forms a weak gel between the surfaces, which collapses on compression. The organization and proper functioning of myelin can be understood in terms of physical noncovalent forces that are optimized at a particular combination of both the amounts of and ratio between the charged lipids and MBP. Thus loss of adhesion, possibly contributing to demyelination, can be brought about by either an excess or deficit of MBP or anionic lipids.biomembrane adhesion ͉ lipid-protein interactions ͉ multiple sclerosis ͉ myelin membrane structure ͉ experimental allergic encephalomyelitis T he myelin sheath is a multilamellar membrane surrounding the axons of neurons in both the central nervous system (CNS) and peripheral nervous system (PNS) (1) as shown in Fig. 1 A and B. The myelin sheath consists of repeating units of double bilayers separated by 3-to 4-nm-thick aqueous layers that alternate between the cytoplasmic and extracellular faces of cell membranes (2) (Fig. 1C). Dehydrated myelin is unusual in that it is composed of 75-80% lipid and 20-25% protein by weight, compared with Ϸ50% of most other cell membranes (3) (Fig. 1 C and D). Multiple lipids make up the myelin sheath (Table 1), and each sheath, with its own distinct physical properties, contributes to the structure, adhesive stability, and possibly the pathogenesis of the myelin membrane. The asymmetric distribution of lipid composition on the cytoplasmic and extracellular faces likely also plays an important role (4). Myelin basic protein (MBP) constitutes 20-30% of total protein by weight and is located only between the 2 cytoplasmic faces, where it acts as an intermembrane adhesion protein.The myelin sheath acts as an electrical insulator, forming a capacitor surrounding the axon, which allows for faster and more efficient conduction of nerve impulses than unmyelinated nerves (5). According to cable theory, the time to transmit a signal over a distance x is ϭ 1 ⁄2RC myelin x 2 , where R is the resistance per unit length, and C myelin is the capacitance between the axon and its surroundings, which is given by (5) C myelin ϭ 2 0 myelin log͑R O /R I ͒ per unit length,where R O and R I are the outer and inner radii (Fig. 1B), 0 is the permittivity of free space, and the mean dielectric constant of the myelin sheath iswhere (Fig. 1C). Low capacitance necessitates a low value of myelin , which is promoted by the much l...

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“…To rule out the possibility that GE3082 was binding to the lipid associated with the MBP complex, the lipids were extracted using Bligh-Dyer extraction method (Bligh and Dyer 1959). The lipids that were extracted by organic solvents when reconstituted in aqueous solution formed multilamellar vesicles (Riccio et al 2000).…”

Section: Development Of An Fp-based Binding Assaymentioning

confidence: 99%

Identification of the Protein Target of Myelin-Binding Ligands by Immunohistochemistry and Biochemical Analyses

Bajaj

LaPlante

Cotero

et al. 2012

J Histochem Cytochem.

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The ability to visualize myelin is important in the diagnosis of demyelinating disorders and the detection of myelin-containing nerves during surgery. The development of myelin-selective imaging agents requires that a defined target for these agents be identified and that a robust assay against the target be developed to allow for assessment of structure-activity relationships. We describe an immunohistochemical analysis and a fluorescence polarization binding assay using purified myelin basic protein (MBP) that provides quantitative evidence that MBP is the molecular binding partner of previously described myelin-selective fluorescent dyes such as BMB, GE3082, and GE3111.

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Multilamellar packing of myelin modeled by lipid-bound MBP

Cited by 35 publications

References 46 publications

An Immunodominant Epitope of Myelin Basic Protein Is an Amphipathic α-Helix

An Immunodominant Epitope of Myelin Basic Protein Is an Amphipathic α-Helix

Interaction forces and adhesion of supported myelin lipid bilayers modulated by myelin basic protein

Identification of the Protein Target of Myelin-Binding Ligands by Immunohistochemistry and Biochemical Analyses

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