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  Structural characterization of copper(II) binding to α-Synuclein: Insights into the bioinorganic chemistry of Parkinson's disease

Rasia, R. M., Bertoncini, C. W., Marsh, D., Hoyer, W., Cherny, D. I., Zweckstetter, M., et al. (2005). Structural characterization of copper(II) binding to α-Synuclein: Insights into the bioinorganic chemistry of Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America, 102: 10.1073/pnas.0407881102, pp. 4294-4299. Retrieved from http://www.pnas.org/content/102/12/4294.full.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0012-E9C5-0 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-80D2-7
Genre: Journal Article

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 Creators:
Rasia, R. M.1, Author              
Bertoncini, C. W.1, Author              
Marsh, D.2, Author              
Hoyer, W.1, Author              
Cherny, D. I.1, Author              
Zweckstetter, M.3, Author              
Griesinger, C.4, Author              
Jovin, T. M.1, Author              
Fernandez, C. O.4, Author              
Affiliations:
1Department of Molecular Biology, MPI for biophysical chemistry, Max Planck Society, ou_578628              
2Department of Spectroscopy and Photochemical Kinetics, MPI for biophysical chemistry, Max Planck Society, ou_578624              
3Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              
4Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              

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Free keywords: amyloid; fibrillation; metallobiology
 Abstract: The aggregation of α -synuclein (AS) is characteristic of Parkinson’s disease and other neurodegenerative synucleinopathies. We demonstrate here that Cu(II) ions are effective in accelerating AS aggregation at physiologically relevant concentrations without altering the resultant fibrillar structures. By using numerous spectroscopic techniques (absorption, CD, EPR, and NMR), we have located the primary binding for Cu(II) to a specific site in the N terminus, involving His-50 as the anchoring residue and other nitrogen oxygen donor atoms in a square planar or distorted tetragonal geometry. The carboxylate-rich C terminus, originally thought to drive copper binding, is able to coordinate a second Cu(II) equivalent, albeit with a 300-fold reduced affinity. The NMR analysis of AS–Cu(II) complexes reveals the existence of conformational restrictions in the native state of the protein. The metallobiology of Cu(II) in Parkinson’s disease is discussed by a comparative analysis with other Cu(II)-binding proteins involved in neurodegenerative disorders.

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Language(s): eng - English
 Dates: 2005-04-042005-03-22
 Publication Status: Published in print
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 Rev. Method: Peer
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Title: Proceedings of the National Academy of Sciences of the United States of America
Source Genre: Journal
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Pages: - Volume / Issue: 102 Sequence Number: 10.1073/pnas.0407881102 Start / End Page: 4294 - 4299 Identifier: -