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Direct observation of the three regions in ?-synuclein that determine its membrane-bound behaviour.

ABSTRACT: ?-synuclein (?S) is a protein involved in neurotransmitter release in presynaptic terminals, and whose aberrant aggregation is associated with Parkinson's disease. In dopaminergic neurons, ?S exists in a tightly regulated equilibrium between water-soluble and membrane-associated forms. Here we use a combination of solid-state and solution NMR spectroscopy to characterize the conformations of ?S bound to lipid membranes mimicking the composition and physical properties of synaptic vesicles. The study shows three ?S regions possessing distinct structural and dynamical properties, including an N-terminal helical segment having a role of membrane anchor, an unstructured C-terminal region that is weakly associated with the membrane and a central region acting as a sensor of the lipid properties and determining the affinity of ?S membrane binding. Taken together, our data define the nature of the interactions of ?S with biological membranes and provide insights into their roles in the function of this protein and in the molecular processes leading to its aggregation.

SUBMITTER: Fusco G

PROVIDER: S-EPMC4046108 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Direct observation of the three regions in α-synuclein that determine its membrane-bound behaviour.

Fusco Giuliana G De Simone Alfonso A Gopinath Tata T Vostrikov Vitaly V Vendruscolo Michele M Dobson Christopher M CM Veglia Gianluigi G

Nature communications 20140529

α-synuclein (αS) is a protein involved in neurotransmitter release in presynaptic terminals, and whose aberrant aggregation is associated with Parkinson's disease. In dopaminergic neurons, αS exists in a tightly regulated equilibrium between water-soluble and membrane-associated forms. Here we use a combination of solid-state and solution NMR spectroscopy to characterize the conformations of αS bound to lipid membranes mimicking the composition and physical properties of synaptic vesicles. The s ...[more]

PMID: 24871041

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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

Direct observation of the three regions in ?-synuclein that determine its membrane-bound behaviour.

Publications

Direct observation of the three regions in α-synuclein that determine its membrane-bound behaviour.

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