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?-Synuclein-induced tubule formation in lipid bilayers.

ABSTRACT: ?-Synuclein is a presynaptic protein that binds to phospholipid membranes and is involved in the pathogenesis of Parkinson's disease (PD). In this paper, we describe the effects of adding wild-type ?-synuclein (WT) and three familial PD mutants (A53T, A30P, and E46K) to membranes containing 15-35 mol % anionic lipid. Tubules were observed to form in the membranes to an extent that depended on the ?-synuclein variant, the anionic lipid content, and the protein concentration. For all four variants, tubule formation decreased with increasing anionic lipid content. Tubules were more readily observed with A30P and E46K than with WT or A53T. The results are consistent with a model wherein the helical content of ?-synuclein increases with increasing anionic lipid content, and ?-synuclein conformers with low helical content have a high propensity to induce tubule formation. This work, combined with previous work from our laboratory (Pandey et al. Biophys. J. 2009, 96, 540), shows that WT adsorption of the protein has deleterious effects on the membrane when the anionic lipid concentration is less than 30 mol % (tubule formation) or greater than 40 mol % (reorganization of the bilayer, clustering of protein).

SUBMITTER: Pandey AP

PROVIDER: S-EPMC3098118 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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α-Synuclein-induced tubule formation in lipid bilayers.

Pandey Anjan P AP Haque Farzin F Rochet Jean-Christophe JC Hovis Jennifer S JS

The journal of physical chemistry. B 20110427 19

α-Synuclein is a presynaptic protein that binds to phospholipid membranes and is involved in the pathogenesis of Parkinson's disease (PD). In this paper, we describe the effects of adding wild-type α-synuclein (WT) and three familial PD mutants (A53T, A30P, and E46K) to membranes containing 15-35 mol % anionic lipid. Tubules were observed to form in the membranes to an extent that depended on the α-synuclein variant, the anionic lipid content, and the protein concentration. For all four variants ...[more]

PMID: 21520980

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Project description:An amyloid form of the protein ?-synuclein is the major component of the intraneuronal inclusions called Lewy bodies, which are the neuropathological hallmark of Parkinson's disease (PD). ?-Synuclein is known to associate with anionic lipid membranes, and interactions between aggregating ?-synuclein and cellular membranes are thought to be important for PD pathology. We have studied the molecular determinants for adsorption of monomeric ?-synuclein to planar model lipid membranes composed of zwitterionic phosphatidylcholine alone or in a mixture with anionic phosphatidylserine (relevant for plasma membranes) or anionic cardiolipin (relevant for mitochondrial membranes). We studied the adsorption of the protein to supported bilayers, the position of the protein within and outside the bilayer, and structural changes in the model membranes using two complementary techniques-quartz crystal microbalance with dissipation monitoring, and neutron reflectometry. We found that the interaction and adsorbed conformation depend on membrane charge, protein charge, and electrostatic screening. The results imply that ?-synuclein adsorbs in the headgroup region of anionic lipid bilayers with extensions into the bulk but does not penetrate deeply into or across the hydrophobic acyl chain region. The adsorption to anionic bilayers leads to a small perturbation of the acyl chain packing that is independent of anionic headgroup identity. We also explored the effect of changing the area per headgroup in the lipid bilayer by comparing model systems with different degrees of acyl chain saturation. An increase in area per lipid headgroup leads to an increase in the level of ?-synuclein adsorption with a reduced water content in the acyl chain layer. In conclusion, the association of ?-synuclein to membranes and its adsorbed conformation are of electrostatic origin, combined with van der Waals interactions, but with a very weak correlation to the molecular structure of the anionic lipid headgroup. The perturbation of the acyl chain packing upon monomeric protein adsorption favors association with unsaturated phospholipids preferentially found in the neuronal membrane.

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?-Synuclein-induced tubule formation in lipid bilayers.

Publications

α-Synuclein-induced tubule formation in lipid bilayers.

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