Michael F Brown
Publications
PMID: 1932556;PMCID: PMC1260117;Abstract:
A partial phase diagram of the ternary system dioleoylphosphatidylethanolamine (DOPE)/sodium cholate/water has been determined using 31P Nuclear Magnetic Resonance (NMR) spectroscopy. In the absence of cholate, it is well known that the DOPE/water system forms a reversed hexagonal (H(II)) phase. We have found that addition of even small amounts of cholate to the DOPE/water system leads to a transition to a lamellar (L(α)) phase. At higher cholate concentrations, a cubic (I) phase (low water content) or a micellar solution (L1) phase (high water content) is present. Thus, cholate molecules have a strong tendency to alter the lipid monolayer curvature. Increasing the concentration of cholate changes the curvature of DOPE from negative (H(II) phase), through zero (L(α) phase), and finally to a phase of positive curvature (micellar solution). This observation can be rationalized in terms of the molecular structure of cholate, which is amphipathic and has one hydrophobic and one hydrophilic side of the steroid ring system. The cholate molecules have a tendency to lie flat on the lipid aggregate surface, thereby increasing the effective interfacial area of the polar head groups, and altering the curvature free energy of the system.
PMID: 23583776;Abstract:
Misfolding and aggregation of the intrinsically disordered protein α-Synuclein (αS) in Lewy body plaques are characteristic markers of late-stage Parkinson's disease. It is well established that membrane binding is initiated at the N-terminus of the protein and affects biasing of conformational ensembles of αS. However, little is understood about the effect of αS on the membrane lipid bilayer. One hypothesis is that intrinsically disordered αS alters the structural properties of the membrane, thereby stabilizing the bilayer against fusion. Here, we used two-dimensional 13C separated local-field NMR to study interaction of the wild-type α-Synuclein (wt-αS) or its N-terminal (1-25) amino acid sequence (N-αS) with a cholesterol-enriched ternary membrane system. This lipid bilayer mimics cellular raft-like domains in the brain that are proposed to be involved in neuronal membrane fusion. The two-dimensional dipolar-recoupling pulse sequence DROSS (dipolar recoupling on-axis with scaling and shape preservation) was implemented to measure isotropic 13C chemical shifts and 13C-1H residual dipolar couplings under magic-angle spinning. Site-specific changes in NMR chemical shifts and segmental order parameters indicate that both wt-αS and N-αS bind to the membrane interface and change lipid packing within raft-like membranes. Mean-torque modeling of 13C-1H NMR order parameters shows that αS induces a remarkable thinning of the bilayer (≈ 6 Å), accompanied by an increase in phospholipid cross-sectional area (≈ 10 Å2). This perturbation is characterized as membrane annealing and entails structural remodeling of the raft-like liquid-ordered phase. We propose this process is implicated in regulation of synaptic membrane fusion that may be altered by aggregation of αS in Parkinson's disease. © 2013 Elsevier Ltd.
PMID: 17951745;Abstract:
Molecular fluctuations are a dominant feature of biomembranes. Cellular functions might rely on these properties in ways yet to be determined. This expectation is suggested by the fact that membrane deformation and rigidity, which govern molecular fluctuations, have been implicated in a number of cellular functions. However, fluctuations are more challenging to measure than average structures, which partially explain the small number of dedicated studies. Here, it is shown that two accessible laboratory methods, small-angle X-ray scattering and solid-state deuterium nuclear magnetic resonance (NMR), can be used as complementary probes of structural fluctuations in lipid membranes. In the case of X-ray scattering, membrane undulations give rise to logarithmically varying positional correlations that generate scattering peaks with long (power-law) tails. In the case of 2H NMR spectroscopy, fluctuations in the magnetic-coupling energies resulting from molecular motions cause relaxation among the various spin energy levels, and yield a powerful probe of orientational fluctuations of the lipid molecules. A unified interpretation of the combined scattering and 2H NMR data is provided by a liquid-crystalline membrane deformation model. The importance of this approach is that it is possible to utilize a microscopic model for positional and orientational observables to calculate bulk material properties of liquid-crystalline systems. © Humana Press Inc.
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