Comparing the copper binding features of alpha and beta synucleins.

Esaú E Rodríguez, Anacelia Ríos, Lidia G Trujano-Ortiz, Atenea Villegas, Gilberto Castañeda-Hernández, Claudio O Fernández, Felipe J González, Liliana Quintanar

Journal of inorganic biochemistry 2022 Apr

filter terms:

Amyloid aggregation of α-synuclein (AS) is one of the hallmarks of Parkinson's disease (PD). Copper ions specifically bind at the N-terminus of AS, accelerating protein aggregation. Its protein homolog β-synuclein (BS) is also a copper binding protein, but it inhibits AS aggregation. Here, a comparative spectroscopic study of the Cu2+ binding properties of AS and BS has been performed, using electronic absorption, circular dichroism (CD) and electronic paramagnetic resonance (EPR). Our comparative spectroscopic study reveals striking similarities between the Cu2+ binding features of the two proteins. The Cu2+ binding site at the N-terminal group of BS protein, modeled by the BS (1-15) fragment is identical to that of AS; however, its rate of reduction is three times faster as compared to the AS site, consistent with BS having an additional Met residue in its Met1-Xn-Met5-Xn-Met10 motif. The latter is also evident in the cyclic voltammetry studies of the Cu-BS complex. On the other hand, the Cu2+ binding features of the His site in both proteins, as modeled by AS(45-55) and BS(60-70), are identical, indicating that the shift in the His position does not affect its coordination features. Finally, replacement of Glu46 by Ala does not alter Cu2+ binding to the His site, suggesting that the familial PD E46K mutation would not impact copper-induced aggregation. While further studies of the redox activity of copper bound to His50 in AS are required to understand the role of this site in metal-mediated aggregation, our study contributes to a better understanding of the bioinorganic chemistry of PD. Copyright © 2022 Elsevier Inc. All rights reserved.

Citation

Esaú E Rodríguez, Anacelia Ríos, Lidia G Trujano-Ortiz, Atenea Villegas, Gilberto Castañeda-Hernández, Claudio O Fernández, Felipe J González, Liliana Quintanar. Comparing the copper binding features of alpha and beta synucleins. Journal of inorganic biochemistry. 2022 Apr;229:111715