Peculiarities of Copper Binding to α-Synuclein

Heavy metals have been implicated as the causative agents for the pathogenesis of the most prevalent neurodegenerative disease. Various mechanisms have been proposed to explain the toxic effects of metals ranging from metal-induced oxidation of protein to metal-induced changes in the protein conformation. Aggregation of a-synuclein is implicated in Parkinson’s disease (PD), and various metals, including copper, constitute a prominent group of α-synuclein aggregation enhancers. In this study, we have systematically characterized the a-synuclein-Cu21 binding sites and analyzed the possible role of metal binding in a-synuclein fibrillation using a set of biophysical techniques, such as electron paramagnetic resonance (EPR), electron spin-echo envelope modulation (ESEEM), circular dichroism (CD), and size exclusion chromatography (SEC). Our analyses indicated that a-synuclein possesses at least two binding sites for Cu21. We have been able to locate one of the binding sites in the N-terminal region. Furthermore, based on the EPR studies of model peptides and β-synuclein, we concluded that the suspected His residue did not appear to participate in strong Cu21 binding.

Key words: α-Synuclein; Aggregation; Fibril; Copper binding.

This article can be cited as:
A. Ahmad, C.S. Burns, A.L. Fink, V.N. Uversky. Peculiarities of Copper Binding to α-Synuclein J. Biomol Struct Dyn 29(4), 825-842 (2012).

Atta Ahmad1,2,6,*
Colin S. Burns1,3,6,*
Anthony L. Fink1,7
Vladimir N. Uversky4,5*

1Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, USA
2Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA
3Department of Chemistry, East Carolina University, Greenville, North Carolina 27858, USA
4Department of Molecular Medicine, College of Medicine, University of South Florida, Tampa, Florida 33612, USA
5Institute for Biological Instrumentation, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia
6Contributed equally.
7Dedicated to the memory of Prof. A. L. Fink.

*Corresponding authors:
E-mail: ahmadatt@umich.edu (AA)
BURNSC@ecu.edu (CB)
vuversky@health.usf.edu (VNU)

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