The N Terminus of α-Synuclein Forms Cu(II)-Bridged Oligomers

Chemistry : a European Journal
Simon C Drew

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.

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Citations

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Jan 30, 2016·Journal of Inorganic Biochemistry·Simon C Drew
Nov 4, 2021·Inorganic Chemistry·Karolina Bossak-AhmadSimon C Drew

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