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The N Terminus of α‐Synuclein Forms Cu II ‐Bridged Oligomers
Author(s) -
Drew Simon C.
Publication year - 2015
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201500236
Subject(s) - electron paramagnetic resonance , chemistry , antiparallel (mathematics) , crystallography , nuclear magnetic resonance spectroscopy , oligomer , stereochemistry , divalent , binding site , intermolecular force , molecule , biochemistry , nuclear magnetic resonance , polymer chemistry , physics , organic chemistry , quantum mechanics , magnetic field
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.