Dataset Information

Effects of curvature and composition on ?-synuclein binding to lipid vesicles.

ABSTRACT: Parkinson's disease is characterized by the presence of intracellular aggregates composed primarily of the neuronal protein ?-synuclein (?S). Interactions between ?S and various cellular membranes are thought to be important to its native function as well as relevant to its role in disease. We use fluorescence correlation spectroscopy to investigate binding of ?S to lipid vesicles as a function of the lipid composition and membrane curvature. We determine how these parameters affect the molar partition coefficient of ?S, providing a quantitative measure of the binding energy, and calculate the number of lipids required to bind a single protein. Specific anionic lipids have a large effect on the free energy of binding. Lipid chain saturation influences the binding interaction to a lesser extent, with larger partition coefficients measured for gel-phase vesicles than for fluid-phase vesicles, even in the absence of anionic lipid components. Although we observe variability in the binding of the mutant proteins, differences in the free energies of partitioning are less dramatic than with varied lipid compositions. Vesicle curvature has a strong effect on the binding affinity, with a >15-fold increase in affinity for small unilamellar vesicles over large unilamellar vesicles, suggesting that ?S may be a curvature-sensing protein. Our findings provide insight into how physical properties of the membrane may modulate interactions of ?S with cellular membranes.

SUBMITTER: Middleton ER

PROVIDER: S-EPMC3042580 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Effects of curvature and composition on α-synuclein binding to lipid vesicles.

Middleton Elizabeth R ER Rhoades Elizabeth E

Biophysical journal 20101001 7

Parkinson's disease is characterized by the presence of intracellular aggregates composed primarily of the neuronal protein α-synuclein (αS). Interactions between αS and various cellular membranes are thought to be important to its native function as well as relevant to its role in disease. We use fluorescence correlation spectroscopy to investigate binding of αS to lipid vesicles as a function of the lipid composition and membrane curvature. We determine how these parameters affect the molar pa ...[more]

PMID: 20923663

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Project description:Proteins anchored to membranes through covalently linked fatty acids and/or isoprenoid groups play crucial roles in all forms of life. Sorting and trafficking of lipidated proteins has traditionally been discussed in the context of partitioning to membrane domains of different lipid composition. We recently showed that membrane shape/curvature can in itself mediate the recruitment of lipidated proteins. However, exactly how membrane curvature and composition synergize remains largely unexplored. Here we investigated how three critical structural parameters of lipids, namely acyl chain saturation, headgroup size, and acyl chain length, modulate the capacity of membrane curvature to recruit lipidated proteins. As a model system we used the lipidated minimal membrane anchor of the GTPase, N-Ras (tN-Ras). Our data revealed complex synergistic effects, whereby tN-Ras binding was higher on planar DOPC than POPC membranes, but inversely higher on curved POPC than DOPC membranes. This variation in the binding to both planar and curved membranes leads to a net increase in the recruitment by membrane curvature of tN-Ras when reducing the acyl chain saturation state. Additionally, we found increased recruitment by membrane curvature of tN-Ras when substituting PC for PE, and when decreasing acyl chain length from 14 to 12 carbons (DMPC versus DLPC). However, these variations in recruitment ability had different origins, with the headgroup size primarily influencing tN-Ras binding to planar membranes whereas the change in acyl chain length primarily affected binding to curved membranes. Molecular field theory calculations recapitulated these findings and revealed lateral pressure as an underlying biophysical mechanism dictating how curvature and composition synergize to modulate recruitment of lipidated proteins. Our findings suggest that the different compositions of cellular compartments could modulate the potency of membrane curvature to recruit lipidated proteins and thereby synergistically regulate the trafficking and sorting of lipidated proteins.

Dataset Information

Effects of curvature and composition on ?-synuclein binding to lipid vesicles.

Publications

Effects of curvature and composition on α-synuclein binding to lipid vesicles.

Similar Datasets

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