title: Structural basis of synaptic vesicle assembly promoted by α-synuclein.
abstract: α-synuclein (αS) is an intrinsically disordered protein whose fibrillar aggregates are the major constituents of Lewy bodies in Parkinson's disease. Although the specific function of αS is still unclear, a general consensus is forming that it has a key role in regulating the process of neurotransmitter release, which is associated with the mediation of synaptic vesicle interactions and assembly. Here we report the analysis of wild-type αS and two mutational variants linked to familial Parkinson's disease to describe the structural basis of a molecular mechanism enabling αS to induce the clustering of synaptic vesicles. We provide support for this 'double-anchor' mechanism by rationally designing and experimentally testing a further mutational variant of αS engineered to promote stronger interactions between synaptic vesicles. Our results characterize the nature of the active conformations of αS that mediate the clustering of synaptic vesicles, and indicate their relevance in both functional and pathological contexts.
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Fusco
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Tillmann
authors.initials: T
authors.lastname: Pape
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK.
authors.forename: Amberley D
authors.initials: AD
authors.lastname: Stephens
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK.
authors.forename: Pierre
authors.initials: P
authors.lastname: Mahou
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Costa
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK.
authors.forename: Clemens F
authors.initials: CF
authors.lastname: Kaminski
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK.
authors.forename: Gabriele S
authors.initials: GS
authors.lastname: Kaminski Schierle
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.affiliation: Department of Chemistry &Department of Biochemistry, Molecular Biology &Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Veglia
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
authors.forename: Alfonso
authors.initials: A
authors.lastname: De Simone
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D004926:Escherichia coli; D056004:Molecular Dynamics Simulation; D051381:Rats; D013572:Synaptic Vesicles / Q000378:metabolism* / Q000648:ultrastructure; D051844:alpha-Synuclein / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein