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α-Synuclein structures from fluorescence energy-transfer kinetics: Implications for the role of the protein in Parkinson's disease

Lee, Jennifer C. and Langen, Ralf and Hummel, Patrick A. and Gray, Harry B. and Winkler, Jay R. (2004) α-Synuclein structures from fluorescence energy-transfer kinetics: Implications for the role of the protein in Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America, 101 (47). pp. 16466-16471. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:LEEpnas04

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Abstract

Parkinson's disease is associated with the deposition and accumulation of alpha-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) alpha-synucleins at physiological pH (7.4), in acidic pH (4.4) solutions, and in the presence of SIDS 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. CID spectra indicate that the protein develops substantial helical structure in the presence of SIDS 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).


Item Type:Article
Additional Information:Copyright © 2004 by the National Academy of Sciences. Contributed by Harry B. Gray, October 4, 2004. This work was supported by the Parkinson’s Disease Foundation (J.R.W.), the National Parkinson Foundation (J.R.W.), the Beckman Macular Research Center (H.B.G. and R.L.), and the Arnold and Mabel Beckman Foundation (H.B.G. and J.R.W.), National Institutes of Health Grants GM068461 (to J.R.W.) and P50 AG05142 (to R.L.), and Department of Energy Grant DE-FG02-02ER15359 (to J.R.W.). J.C.L. thanks the Arnold and Mabel Beckman Foundation for a Beckman Senior Research Fellowship.
Subject Keywords:TRYPTOPHAN, 3-NITROTYROSINE, TIME-RESOLVED FLUORESCENCE, A-BETA COMPONENT, FIBRIL FORMATION, LEWY BODIES, ALZHEIMERS-DISEASE, MEMBRANE INTERACTIONS, PRECURSOR PROTEIN, LINKED MUTATIONS, DYNAMICS, BRAIN
Record Number:CaltechAUTHORS:LEEpnas04
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:LEEpnas04
Alternative URL:http://dx.doi.org/10.1073/pnas.0407307101
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:954
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:15 Nov 2005
Last Modified:14 Nov 2014 19:18

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