Effect of bovine basic protein charge microheterogeneity on protein-induced aggregation of unilamellar vesicles containing a mixture of acidic and neutral phospholipids

Cheifetz, Sela; Moscarello, Mario A.

doi:10.1021/bi00329a016

Cited by 110 publications

(77 citation statements)

References 28 publications

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“…To disperse the lipids, the following solvents were purchased from Sigma-Aldrich: chloroform (CHROMASOLV Plus for HPLC, purity ≥99.9%), hexane (RegentPlus, purity ≥99.0%), ethanol (200 proof, HPLC/spectrophotometric grade), and methanol (CHROMASOLV Plus for HPLC, purity ≥99.9%). MBP was isolated from bovine brain white matter (51) and kept in a deep freezer (−50°C) until use.…”

Section: Methodsmentioning

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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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: Methodsmentioning

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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“…Dipalmitoylphosphatidylethanolamine (DPPE), sodium nitrate, calcium nitrate, and morpholinepropanesulfonic acid (Mops) sodium salt were purchased from Sigma-Aldrich. MBP was isolated from bovine-brain white matter as described (35). The MBP used was unfractionated, heterogeneous, bovine MBP.…”

Section: Methodsmentioning

confidence: 99%

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.

151

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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“…MBP was prepared by the method of Cheifetz and Moscarello. 17 The charge isomers were isolated on CM52 columns as described by us. 6 Normal human brain was obtained from the Canadian Brain Tissue Bank.…”

Section: Methodsmentioning

confidence: 99%

Myelin localization of peptidylarginine deiminases 2 and 4: comparison of PAD2 and PAD4 activities

Wood

Ackerley

Brand

et al. 2008

Laboratory Investigation

112

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An understanding of the structure and composition of the myelin sheath is essential to understand the pathogenesis of demyelinating diseases such as multiple sclerosis (MS). The presence of citrulline in myelin proteins in particular myelin basic protein (MBP) causes an important change in myelin structure, which destabilizes myelin. The peptidylarginine deiminases (PADs) are responsible for converting arginine in proteins to citrulline. Two of these, PAD2 and PAD4, were localized to the myelin sheath by immunogold electron microscopy. Deimination of MBP by the recombinant forms of these enzymes showed that it was extensive, that is, PAD2 deiminated 18 of 19 arginyl residues in MBP, whereas PAD4 deiminated 14 of 19 residues. In the absence of PAD2 (the PAD2-knockout mouse) PAD4 remained active with limited deimination of arginyl residues. In myelin isolated from patients with MS, the amounts of both PAD2 and PAD4 enzymes were increased compared with that in normals, and the citrullinated proteins were also increased. These data support the view that an increase in citrullinated proteins resulting from increased PAD2 and 4 is an important change in the pathogenesis of MS. Peptidylarginine deiminases (PADs) are enzymes which deiminate arginyl residues in proteins. Five isozymes, termed PADs 1-4 and PAD6, are known, which have some tissue specificity, although PAD2 is widely distributed. 1 It is the principal PAD enzyme in brain, where it has been shown to be responsible for the deimination of arginyl residues in myelin basic protein (MBP), a principal protein in myelin 2 and a possible autoantigen in multiple sclerosis (MS). 3,4 The presence of other PAD enzymes in myelin has not been reported. For all PADs, the deimination reaction involves the conversion of arginyl residues in proteins to citrulline and the formation of ammonia. 5 The conversion of arginine to citrulline involves the loss of one positive charge from the protein for each arginine deiminated.In earlier studies, we reported that MBP isolated from white matter from normal human brain could be fractionated into several components by column chromatography. One of these components, which accounted for 20% of all the MBP, contained six citrullinyl residues, the sites of which we determined by protein sequencing. 6 More recently, the deimination has been shown to be more extensive by mass spectrometry with partial deimination of many arginines. 7 The loss of six positive charges accounted for the chromatographic behavior on the cation-exchange column. This same fraction isolated from patients with MS accounted for 45% of the total MBP, and in a case of fulminating MS, it accounted for 80-90% of all the MBP. 8 Instead of six arginyl residues in normal MBP, 6 18 of 19 arginyl residues in the Marburg's MBP were deiminated. In a number of in vitro studies in protein-lipid interaction systems, we showed that this deiminated protein was unable to compact lipid bilayers, causing destabilization, which might be the mechanism of demyelination. 9 Our recent studie...

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Effect of bovine basic protein charge microheterogeneity on protein-induced aggregation of unilamellar vesicles containing a mixture of acidic and neutral phospholipids

Cited by 110 publications

References 28 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

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

Myelin localization of peptidylarginine deiminases 2 and 4: comparison of PAD2 and PAD4 activities

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