Coordination features and affinity of the Cu(2)+ site in the alpha-synuclein protein of Parkinson's disease.
Article Details
- CitationCopy to clipboard
Dudzik CG, Walter ED, Millhauser GL
Coordination features and affinity of the Cu(2)+ site in the alpha-synuclein protein of Parkinson's disease.
Biochemistry. 2011 Mar 22;50(11):1771-7. doi: 10.1021/bi101912q. Epub 2011 Feb 14.
- PubMed ID
- 21319811 [ View in PubMed]
- Abstract
Parkinson's disease (PD) is the second most prevalent age-related, neurodegenerative disorder, affecting >1% of the population over the age of 60. PD pathology is marked by intracellular inclusions composed primarily of the protein alpha-synuclein (alpha-syn). These inclusions also contain copper, and the interaction of Cu(2+) with alpha-syn may play an important role in PD fibrillogenesis. Here we report the stoichiometry, affinity, and coordination structure of the Cu(2+)-alpha-syn complex. Electron paramagnetic resonance (EPR) titrations show that monomeric alpha-syn binds 1.0 equiv of Cu(2+) at the protein N-terminus. Next, an EPR competition technique demonstrates that alpha-syn binds Cu(2+) with a K(d) of approximately 0.10 nM. Finally, EPR and electron spin echo modulation (ESEEM) applied to a suite of mutant and truncated alpha-syn constructs reveal a coordination sphere arising from the N-terminal amine, the Asp2 amide backbone and side chain carboxyl group, and the His50 imidazole. The high binding affinity identified here, in accord with previous measurements, suggests that copper uptake and sequestration may be a part of alpha-syn's natural function, perhaps modulating copper's redox properties. The findings further suggest that the long-range interaction between the N-terminus and His50 may have a weakening effect on the interaction of alpha-syn with lipid membranes, thereby mobilizing monomeric alpha-syn and hastening fibrillogenesis.