?-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation.

ABSTRACT: Physiologically, ?-synuclein chaperones soluble NSF attachment protein receptor (SNARE) complex assembly and may also perform other functions; pathologically, in contrast, ?-synuclein misfolds into neurotoxic aggregates that mediate neurodegeneration and propagate between neurons. In neurons, ?-synuclein exists in an equilibrium between cytosolic and membrane-bound states. Cytosolic ?-synuclein appears to be natively unfolded, whereas membrane-bound ?-synuclein adopts an ?-helical conformation. Although the majority of studies showed that cytosolic ?-synuclein is monomeric, it is unknown whether membrane-bound ?-synuclein is also monomeric, and whether chaperoning of SNARE complex assembly by ?-synuclein involves its cytosolic or membrane-bound state. Here, we show using chemical cross-linking and fluorescence resonance energy transfer (FRET) that ?-synuclein multimerizes into large homomeric complexes upon membrane binding. The FRET experiments indicated that the multimers of membrane-bound ?-synuclein exhibit defined intermolecular contacts, suggesting an ordered array. Moreover, we demonstrate that ?-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 ?-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.

SUBMITTER: Burre J 

PROVIDER: S-EPMC4210039 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature