Dataset Information

Membrane-Bound Alpha Synuclein Clusters Induce Impaired Lipid Diffusion and Increased Lipid Packing.

ABSTRACT: The aggregation of membrane-bound ?-synuclein (?S) into oligomers and/or amyloid fibrils has been suggested to cause membrane damage in in vitro model phospholipid membrane systems and in vivo. In this study, we investigate how ?S interactions that precede the formation of well-defined aggregates influence physical membrane properties. Using three truncated variants of ?S with different aggregation propensities and comparable phospholipid membrane binding affinities we show, using fluorescence recovery after photobleaching (FRAP) and fluorescence anisotropy measurements, that formation of ?S clusters on supported lipid bilayers (SLBs) impairs lateral lipid diffusion and increases lipid packing beneath the ?S clusters. Formation of protein clusters starts immediately after monomer addition. The magnitudes of the changes in effective lipid diffusion and lipid order increase with the protein cluster size. Our results show that the combination of inter-?S and ?S-membrane interactions can drive the formation of more ordered lipid domains. Considering the functional involvement of membrane micro-domains in biological membranes, ?S-induced domain formation may be relevant for alternative disease mechanisms.

SUBMITTER: Iyer A

PROVIDER: S-EPMC5153541 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Membrane-Bound Alpha Synuclein Clusters Induce Impaired Lipid Diffusion and Increased Lipid Packing.

Iyer Aditya A Schilderink Nathalie N Claessens Mireille M A E MMAE Subramaniam Vinod V

Biophysical journal 20161201 11

The aggregation of membrane-bound α-synuclein (αS) into oligomers and/or amyloid fibrils has been suggested to cause membrane damage in in vitro model phospholipid membrane systems and in vivo. In this study, we investigate how αS interactions that precede the formation of well-defined aggregates influence physical membrane properties. Using three truncated variants of αS with different aggregation propensities and comparable phospholipid membrane binding affinities we show, using fluorescence r ...[more]

PMID: 27926845

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Project description:Membrane-induced disorder-to-helix transition of α-synuclein, a presynaptic protein, has been implicated in a number of important neuronal functions as well as in the etiology of Parkinson's disease. In order to obtain structural insights of membrane-bound α-synuclein at the residue-specific resolution, we took advantage of the fact that the protein is devoid of tryptophan and incorporated single tryptophan at various residue positions along the sequence. These tryptophans were used as site-specific markers to characterize the structural and dynamical aspects of α-synuclein on the negatively charged small unilamellar lipid vesicles. An array of site-specific fluorescence readouts, such as the spectral-shift, quenching efficiency and anisotropy, allowed us to discern various features of the conformational rearrangements occurring at different locations of α-synuclein on the lipid membrane. In order to define the spatial localization of various regions of the protein near the membrane surface, we utilized a unique and sensitive indicator, namely, red-edge excitation shift (REES), which originates when a fluorophore is located in a highly ordered micro-environment. The extent of REES observed at different residue positions allowed us to directly identify the residues that are localized at the membrane-water interface comprising a thin (∼ 15 Å) layer of motionally restrained water molecules and enabled us to construct a dynamic hydration map of the protein. The combination of site-specific fluorescence readouts allowed us to unravel the intriguing molecular details of α-synuclein on the lipid membrane in a direct model-free fashion. Additionally, the combination of methodologies described here are capable of distinguishing subtle but important structural alterations of α-synuclein bound to different negatively charged lipids with varied head-group chemistry. We believe that the structural modulations of α-synuclein on the membrane could potentially be related to its physiological functions as well as to the onset of Parkinson's diseases.

Dataset Information

Membrane-Bound Alpha Synuclein Clusters Induce Impaired Lipid Diffusion and Increased Lipid Packing.

Publications

Membrane-Bound Alpha Synuclein Clusters Induce Impaired Lipid Diffusion and Increased Lipid Packing.

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