期刊
JOURNAL OF INORGANIC BIOCHEMISTRY
卷 141, 期 -, 页码 208-211出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2014.08.012
关键词
Parkinson; Alpha-synuclein; Cu(I); Met-rich sites
资金
- ANPCyT
- FONCyT
- CONICET
- Ministry of Education of Argentina
- Ministry of Health of Argentina [PICT 1344, PICT 2819]
- Max Planck Society [10390]
- Alexander von Humboldt Foundation [P.S.BICH 4507]
- CONICET in Argentina
The aggregation of alpha-synuclein (AS) is a critical step in the etiology of Parkinson's disease (PD) and other neurodegenerative synucleinopathies. This process is selectively enhanced by copper in vitro and the interaction is proposed to play a potential role in vivo. Presently, the identity of the Cu(I) binding sites in AS and their relative affinities are under debate. In this work we have addressed unresolved details related to the structural binding specificity and affinity of Cu(I) to full-length AS. We demonstrated conclusively that: (i) the binding preferences of Cu(I) for the Met-binding sites at the N- (K-d = 20 mu M) and C-terminus (K-d = 270 mu M) of AS are widely different: (ii) the imidazole ring of His-50 acts as an effective anchoring residue (K-d = 50 mu M) for Cu(I) binding to AS; and (iii) no major structural rearrangements occur in the protein upon Cu(I) binding. Overall, our work shows that Cu(I) binding to the N- and C-terminal regions of AS are two independent events, with substantial differences in their affinities, and suggest that protein oxidative damage derived from a misbalance in cellular copper homeostasis would target preferentially the N-terminal region of AS. This knowledge is key to understanding the structural-aggregation basis of the copper catalyzed oxidation of AS. (C) 2014 Elsevier Inc. All rights reserved.
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