Synergistic interactions of lipids and myelin basic protein

Abstract

This report describes force measurements and atomic force microscope imaging of lipid-protein interactions that determine the structure of a model membrane system that closely mimics the myelin sheath. Our results suggest that noncovalent, mainly electrostatic and hydrophobic, interactions are responsible for the multilamellar structure and stability of myelin. We find that myelin basic protein acts as a lipid coupler between two apposed bilayers and as a lipid ''hole-filler,'' effectively preventing defect holes from developing. From our protein-mediated-adhesion and forcedistance measurements, we develop a simple quantitative model that gives a reasonably accurate picture of the molecular mechanism and adhesion of bilayer-bridging proteins by means of noncovalent interactions. The results and model indicate that optimum myelin adhesion and stability depend on the difference between, rather than the product of, the opposite charges on the lipid bilayers and myelin basic protein, as well as on the repulsive forces associated with membrane fluidity, and that small changes in any of these parameters away from the synergistically optimum values can lead to large changes in the adhesion or even its total elimination. Our results also show that the often-asked question of which membrane species, the lipids or the proteins, are the ''important ones'' may be misplaced. Both components work synergistically to provide the adhesion and overall structure. A better appreciation of the mechanism of this synergy may allow for a better understanding of stacked and especially myelin membrane structures and may lead to better treatments for demyelinating diseases such as multiple sclerosis.lipid-protein interactions ͉ myelin membrane structure ͉ membrane adhesion ͉ membrane regeneration͞healing ͉ demyelinating diseases T his communication addresses the general question of the molecular interactions that determine the structure and stability of membranes that are stabilized by bridging proteins, with the myelin sheath of the central nervous system (CNS) being taken as a prime example of this type of structure. The myelin sheath is formed by extensions of oligodendrocyte cell membranes that wrap around the axon to form a cylindrical scroll a few tens of micrometers in diameter (1, 2). The sheath consists of repeat units of ''double'' bilayers separated by 3-to 4-nm-thick aqueous layers that alternate between the cytoplasmic and extracellular spaces (2). Seventy to 80% of the dry weight of myelin consists of lipids, a proportion that is significantly higher than in most other cell membranes. There are two major proteins: myelin basic protein (MBP), which spans the aqueous cytoplasmic spaces, and proteolipid protein, which spans the bilayers (2). Myelin acts as a transmitter of electric signals known as action potentials, its efficiency being attributed to the low dielectric constant associated with the high lipid content of its closely apposed membranes. Electrical impulses are transmitted along myelinated axons orders of magnitude...

Microstructural analysis of the effects of incorporation of myelin basic protein in phospholipid layers

“…The mechanism we propose for MBP adsorption may support the model according to which MBP works as a glue for adjacent bilayers of the myelin sheath, as also confirmed in recent work (Hu et al 2004) which, using force measurements and scanning microscopy, suggests that MBP acts as a lipid coupler between bilayers and as a lipid ''hole filler'' through noncovalent, mainly electrostatic and hydrophobic interactions. In fact, our reflectivity data provide microscopic confirmation of a large body of results and conjectures leading to the mechanism that the protein binds to polar head groups of adjacent bilayers and forms a bridge between them through polar or electrostatic attraction.…”

Structural Transition in Myelin Membrane as Initiator of Multiple Sclerosis

“…31 Little is known about the intermolecular interactions and structural organization within myelin sheaths. 32−34 A recent study showed that MBP regulates differently the diffusion rate of specific lipids within the myelin.…”

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

“…Many attempts (10,13,14) have been made to experimentally observe the molecular interactions (forces) between myelin lipids and MBP. However, no techniques have quantified how electrostatic interactions (namely, double-layer, coulombic or ionic bonds, and salt bridges), which can be attractive or repulsive, and attractive van der Waals and hydrophobic interactions act across the cytoplasmic and extracellular spaces of myelin to ensure the integrity of its structure.…”

“…To determine whether changes in the lipid or MBP concentration or mole fraction affect the adhesion of the cytoplasmic faces of the myelin sheath, we compared the forces between model bilayers of lipid mixtures that reflect the composition of EAE myelin in the common marmoset and of normal, healthy myelin (10,14). Model membranes with the composition of the cytoplasmic side of EAE myelin (see Table 1) were constructed on mica surfaces by Langmuir-Blodgett (LB) deposition, and the forces between the membranes were measured by using a surface forces apparatus (SFA) after exposure to various solution concentrations of MBP.…”