Interplay of alpha-synuclein binding and conformational switching probed by single-molecule fluorescence

Ferreon, Allan Chris M., Gambin, Yann, Lemke, Edward A. and Deniz, Ashok A. (2009) Interplay of alpha-synuclein binding and conformational switching probed by single-molecule fluorescence. Proceedings of the National Academy of Sciences of the United States of America, 106 14: 5645-5650. doi:10.1073/pnas.0809232106


Author Ferreon, Allan Chris M.
Gambin, Yann
Lemke, Edward A.
Deniz, Ashok A.
Title Interplay of alpha-synuclein binding and conformational switching probed by single-molecule fluorescence
Formatted title
Interplay of α-synuclein binding and conformational switching probed by single-molecule fluorescence
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2009-04-07
Sub-type Article (original research)
DOI 10.1073/pnas.0809232106
Open Access Status Not Open Access
Volume 106
Issue 14
Start page 5645
End page 5650
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Abstract We studied the coupled binding and folding of α-synuclein, an intrinsically disordered protein linked with Parkinson's disease. Using single-molecule fluorescence resonance energy transfer and correlation methods, we directly probed protein membrane association, structural distributions, and dynamics. Results revealed an intricate energy landscape on which binding of α-synuclein to amphiphilic small molecules or membrane-like partners modulates conformational transitions between a natively unfolded state and multiple α-helical structures. α-Synuclein conformation is not continuously tunable, but instead partitions into 2 main classes of folding landscape structural minima. The switch between a broken and an extended helical structure can be triggered by changing the concentration of binding partners or by varying the curvature of the binding surfaces presented by micelles or bilayers composed of the lipid-mimetic SDS. Single-molecule experiments with lipid vesicles of various composition showed that a low fraction of negatively charged lipids, similar to that found in biological membranes, was sufficient to drive α-synuclein binding and folding, resulting here in the induction of an extended helical structure. Overall, our results imply that the 2 folded structures are preencoded by the α-synuclein amino acid sequence, and are tunable by small-molecule supramolecular states and differing membrane properties, suggesting novel control elements for biological and amyloid regulation of α-synuclein.
Keyword Amyloid
Misfolding
Parkinson’s disease
Protein folding
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: ERA 2012 Admin Only
Institute for Molecular Bioscience - Publications
 
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Created: Thu, 13 Oct 2011, 22:28:50 EST by Yann Gambin on behalf of Institute for Molecular Bioscience