title: The N Terminus of α-Synuclein Forms Cu(II)-Bridged Oligomers.
abstract: The oligomerization of α-synuclein (αSyn) is one of the defining features of Parkinson's disease. Binding of divalent copper to the N terminus of αSyn has been implicated in both its function and dysfunction. Herein, the molecular details of the Cu(II) /αSyn binding interface have been revealed using a library of synthetic 56-residue αSyn peptides containing site-specific isotopic labels. Using electron paramagnetic resonance spectroscopy, αSyn is shown to coordinate Cu(II) with high affinity via two pH-dependent coordination modes between pH 6.5-8.5. Most remarkably, the data demonstrate that the dominant mode is associated with binding to oligomers (antiparallel dimers and/or cyclic trimers) in which Cu(II) ions occupy intermolecular bridging sites. The findings provide a molecular link between Cu(II) -bound αSyn and its associated quaternary oligomeric structure.
authors.affiliation: Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, 3010 (Australia). sdrew@unimelb.edu.au.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Drew
mesh_terms: D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D010300:Parkinson Disease / Q000378:metabolism; D011485:Protein Binding; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
chemical_list: D051844:alpha-Synuclein; D003300:Copper
keywords: EPR spectroscopy; copper; isotopic labeling; oligomers; synuclein