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214024.0 [No comment] 09.04.2009 14:51 Released

ID: 214024.0, MPI für biophysikalische Chemie / Molekulare Biologie (Dr. Thomas M. Jovin)
Structural characterization of copper(II) binding to α-Synuclein: Insights into the bioinorganic chemistry of Parkinson's disease
Authors:Rasia, R. M.; Bertoncini, C. W.; Marsh, D.; Hoyer, W.; Cherny, D. I.; Zweckstetter, M.; Griesinger, C.; Jovin, T. M.; Fernandez, C. O.
Date of Publication (YYYY-MM-DD):2005-03-22
Title of Journal:Proceedings of the National Academy of Sciences of the United States of America
Start Page:4294
End Page:4299
Sequence Number of Article:doi:10.1073/pnas.0407881102
Review Status:Peer-review
Audience:Not Specified
Abstract / Description: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.
Free Keywords:amyloid; fibrillation; metallobiology
Last Change of the Resource (YYYY-MM-DD):2005-04-04
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für biophysikalische Chemie/Abt. Thomas Jovin / 060
MPI für biophysikalische Chemie/AG Markus Zweckstetter
MPI für biophysikalische Chemie/Abt. Christian Griesinger / 030
MPI für biophysikalische Chemie/Abt. Jürgen Troe / 010