title: α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation.
abstract: Physiologically, α-synuclein chaperones soluble NSF attachment protein receptor (SNARE) complex assembly and may also perform other functions; pathologically, in contrast, α-synuclein misfolds into neurotoxic aggregates that mediate neurodegeneration and propagate between neurons. In neurons, α-synuclein exists in an equilibrium between cytosolic and membrane-bound states. Cytosolic α-synuclein appears to be natively unfolded, whereas membrane-bound α-synuclein adopts an α-helical conformation. Although the majority of studies showed that cytosolic α-synuclein is monomeric, it is unknown whether membrane-bound α-synuclein is also monomeric, and whether chaperoning of SNARE complex assembly by α-synuclein involves its cytosolic or membrane-bound state. Here, we show using chemical cross-linking and fluorescence resonance energy transfer (FRET) that α-synuclein multimerizes into large homomeric complexes upon membrane binding. The FRET experiments indicated that the multimers of membrane-bound α-synuclein exhibit defined intermolecular contacts, suggesting an ordered array. Moreover, we demonstrate that α-synuclein promotes SNARE complex assembly at the presynaptic plasma membrane in its multimeric membrane-bound state, but not in its monomeric cytosolic state. Our data delineate a folding pathway for α-synuclein that ranges from a monomeric, natively unfolded form in cytosol to a physiologically functional, multimeric form upon membrane binding, and show that only the latter but not the former acts as a SNARE complex chaperone at the presynaptic terminal, and may protect against neurodegeneration.
authors.affiliation: Department of Molecular and Cellular Physiology and.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Burré
authors.affiliation: Department of Molecular and Cellular Physiology and.
authors.forename: Manu
authors.initials: M
authors.lastname: Sharma
authors.affiliation: Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University Medical School, Stanford, CA 94305 tcs1@stanford.edu.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D015151:Immunoblotting; D008081:Liposomes / Q000378:metabolism; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D050600:SNARE Proteins / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D008081:Liposomes; D046912:Multiprotein Complexes; D010743:Phospholipids; D050600:SNARE Proteins; D050988:Vesicle-Associated Membrane Protein 2; D051844:alpha-Synuclein
keywords: Parkinson's disease; SNARE proteins; membrane fusion; synapse