title: α-Synuclein senses lipid packing defects and induces lateral expansion of lipids leading to membrane remodeling.
abstract: There is increasing evidence for the involvement of lipid membranes in both the functional and pathological properties of α-synuclein (α-Syn). Despite many investigations to characterize the binding of α-Syn to membranes, there is still a lack of understanding of the binding mode linking the properties of lipid membranes to α-Syn insertion into these dynamic structures. Using a combination of an optical biosensing technique and in situ atomic force microscopy, we show that the binding strength of α-Syn is related to the specificity of the lipid environment (the lipid chemistry and steric properties within a bilayer structure) and to the ability of the membranes to accommodate and remodel upon the interaction of α-Syn with lipid membranes. We show that this interaction results in the insertion of α-Syn into the region of the headgroups, inducing a lateral expansion of lipid molecules that can progress to further bilayer remodeling, such as membrane thinning and expansion of lipids out of the membrane plane. We provide new insights into the affinity of α-Syn for lipid packing defects found in vesicles of high curvature and in planar membranes with cone-shaped lipids and suggest a comprehensive model of the interaction between α-Syn and lipid bilayers. The ability of α-Syn to sense lipid packing defects and to remodel membrane structure supports its proposed role in vesicle trafficking.
authors.affiliation: From the Nanoscience Centre, Department of Engineering, University of Cambridge, Cambridge CB3 0FF, United Kingdom,. Electronic address: mmo25@cam.ac.uk.
authors.forename: Myriam M
authors.initials: MM
authors.lastname: Ouberai
authors.affiliation: the Farfield Group Ltd., Biolin Scientific, Voyager, Chicago Avenue, Manchester M90 3DQ, United Kingdom, and.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: the Farfield Group Ltd., Biolin Scientific, Voyager, Chicago Avenue, Manchester M90 3DQ, United Kingdom, and.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Swann
authors.affiliation: the Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Celine
authors.initials: C
authors.lastname: Galvagnion
authors.affiliation: the Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Tim
authors.initials: T
authors.lastname: Guilliams
authors.affiliation: the Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: From the Nanoscience Centre, Department of Engineering, University of Cambridge, Cambridge CB3 0FF, United Kingdom.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Welland
mesh_terms: D007368:Interferometry; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D008555:Melitten / Q000378:metabolism; D008563:Membrane Lipids / Q000737:chemistry*; D008565:Membrane Proteins / Q000378:metabolism; D008958:Models, Molecular; D010539:Permeability; D010743:Phospholipids / Q000737:chemistry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D014020:Tissue Extracts; D053835:Unilamellar Liposomes / Q000737:chemistry / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008051:Lipid Bilayers; D008563:Membrane Lipids; D008565:Membrane Proteins; D010743:Phospholipids; D014020:Tissue Extracts; D053835:Unilamellar Liposomes; D051844:alpha-Synuclein; D008555:Melitten
keywords: Atomic Force Microscopy; Dual Polarization Interferometry; Lipid Packing Defects; Membrane Bilayer; Membrane Biophysics; Membrane Remodeling; Membrane Structure; Protein-Lipid Interactions; alpha-Synuclein