Counteracting chemical chaperone effects on the single-molecule alpha-synuclein structural landscape

Ferreon, Allan Chris M., Moosa, Mahdi Muhammad, Gambin, Yann and Deniz, Ashok A. (2012) Counteracting chemical chaperone effects on the single-molecule alpha-synuclein structural landscape. Proceedings of the National Academy of Sciences of the United States of America, 109 44: 17826-17831. doi:10.1073/pnas.1201802109


Author Ferreon, Allan Chris M.
Moosa, Mahdi Muhammad
Gambin, Yann
Deniz, Ashok A.
Title Counteracting chemical chaperone effects on the single-molecule alpha-synuclein structural landscape
Formatted title
Counteracting chemical chaperone effects on the single-molecule α-synuclein structural landscape
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 2012-10-30
Sub-type Article (original research)
DOI 10.1073/pnas.1201802109
Open Access Status
Volume 109
Issue 44
Start page 17826
End page 17831
Total pages 6
Editor Peter G. Wolyne
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Subject 1000 General
Formatted abstract
Protein structure and function depend on a close interplay between intrinsic folding energy landscapes and the chemistry of the protein environment. Osmolytes are small-molecule compounds that can act as chemical chaperones by altering the environment in a cellular context. Despite their importance, detailed studies on the role of these chemical chaperones in modulating structure and dimensions of intrinsically disordered proteins have been limited. Here, we used single-molecule Förster resonance energy transfer to test the counteraction hypothesis of counterbalancing effects between the protecting osmolyte trimethylamine-N-oxide (TMAO) and denaturing osmolyte urea for the case of α-synuclein, a Parkinson’s disease-linked protein whose monomer exhibits significant disorder. The single-molecule experiments, which avoid complications from protein aggregation, do not exhibit clear solvent-induced cooperative protein transitions for these osmolytes, unlike results from previous studies on globular proteins. Our data demonstrate the ability of TMAO and urea to shift α-synuclein structures towards either more compact or expanded average dimensions. Strikingly, the experiments directly reveal that a 2∶1 [urea]∶[TMAO] ratio has a net neutral effect on the protein’s dimensions, a result that holds regardless of the absolute osmolyte concentrations. Our findings shed light on a surprisingly simple aspect of the interplay between urea and TMAO on α-synuclein in the context of intrinsically disordered proteins, with potential implications for the biological roles of such chemical chaperones. The results also highlight the strengths of single-molecule experiments in directly probing the chemical physics of protein structure and disorder in more chemically complex environments.
Keyword Parkinson's disease
Protein folding
Urea-TMAO counteraction
SmFRET
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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