title: Direct observation of the three regions in α-synuclein that determine its membrane-bound behaviour.
abstract: 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 study shows three αS 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 αS membrane binding. Taken together, our data define the nature of the interactions of αS with biological membranes and provide insights into their roles in the function of this protein and in the molecular processes leading to its aggregation.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Fusco
authors.affiliation: Department of Life Sciences, Imperial College London, South Kensington, London SW7 2AZ, UK.
authors.forename: Alfonso
authors.initials: A
authors.lastname: De Simone
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall 321 Church street SE, Minneapolis, Minnesota 55455, USA.
authors.forename: Tata
authors.initials: T
authors.lastname: Gopinath
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall 321 Church street SE, Minneapolis, Minnesota 55455, USA.
authors.forename: Vitaly
authors.initials: V
authors.lastname: Vostrikov
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: 1] Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall 321 Church street SE, Minneapolis, Minnesota 55455, USA [2] Department of Chemistry, University of Minnesota, 6-155 Jackson Hall 321 Church street SE, Minneapolis, Minnesota 55455, USA.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Veglia
mesh_terms: D002462:Cell Membrane / Q000378:metabolism*; D008051:Lipid Bilayers / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D011485:Protein Binding; D017433:Protein Structure, Secondary; D053835:Unilamellar Liposomes / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D008051:Lipid Bilayers; D008055:Lipids; D053835:Unilamellar Liposomes; D051844:alpha-Synuclein