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α-Synuclein Structures from Fluorescence Energy-Transfer Kinetics: Implications for the Role of the Protein in Parkinson's Disease
Jennifer C. Lee, Ralf Langen, Patrick A. Hummel, Harry B. Gray and Jay R. Winkler
Proceedings of the National Academy of Sciences of the United States of America
Vol. 101, No. 47 (Nov. 23, 2004), pp. 16466-16471
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/3373848
Page Count: 6
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Parkinson's disease is associated with the deposition and accumulation of α-synuclein fibrils in the brain. A30P and A53T mutations have been linked to the early-onset familial disease state. Time-resolved tryptophan fluorescence energy-transfer measurements have been used to probe the structures of pseudo-wild-type and mutant (A30P) α-synucleins at physiological pH (7.4), in acidic pH (4.4) solutions, and in the presence of SDS micelles, a membrane mimic. Fluorescent donor-energy acceptor (DA) distance distributions for six different tryptophan/3-nitro-tyrosine pairs reveal the presence of compact, intermediate, and extended conformations of the protein. CD spectra indicate that the protein develops substantial helical structure in the presence of SDS micelles. DA distributions show that micelles induce compaction in the N-terminal region and expansion of the acidic C terminus. In acidic solutions, there is an increased population of collapsed structures in the C-terminal region. Energy-transfer measurements demonstrate that the average DA distances for the W4-Y19 and Y19-W39 pairs are longer in one of the two disease-related mutants (A30P).
Proceedings of the National Academy of Sciences of the United States of America © 2004 National Academy of Sciences