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Protein Science (2008), 17:887-898. Published by Cold Spring Harbor Laboratory Press. Copyright © 2008 The Protein Society
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Molecular determinants of the aggregation behavior of {alpha}- and β-synuclein

Robert C. Rivers1, Janet R. Kumita1, Gian Gaetano Tartaglia1, Matthew M. Dedmon1, Amol Pawar1, Michele Vendruscolo1, Christopher M. Dobson1, and John Christodoulou1,3

1 Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom
2 Institute of Structural Molecular Biology, Research Department of Structural and Molecular Biology, University College London, London WC1E 6BT, United Kingdom
3 School of Crystallography, Birbeck College, London WC1E 6BT, United Kingdom

(RECEIVED August 16, 2007; FINAL REVISION December 14, 2007; ACCEPTED December 20, 2007)

{alpha}- and β-synuclein are closely related proteins, the first of which is associated with deposits formed in neurodegenerative conditions such as Parkinson's disease while the second appears to have no relationship to any such disorders. The aggregation behavior of {alpha}- and β-synuclein as well as a series of chimeric variants were compared by exploring the structural transitions that occur in the presence of a widely used lipid mimetic, sodium dodecyl sulfate (SDS). We found that the aggregation rates of all these protein variants are significantly enhanced by low concentrations of SDS. In particular, we inserted the 11-residue sequence of mainly hydrophobic residues from the non-amyloid-β-component (NAC) region of {alpha}-synuclein into β-synuclein and show that the fibril formation rate of this chimeric protein is only weakly altered from that of β-synuclein. These intrinsic propensities to aggregate are rationalized to a very high degree of accuracy by analysis of the sequences in terms of their associated physicochemical properties. The results begin to reveal that the differences in behavior are primarily associated with a delicate balance between the positions of a range of charged and hydrophobic residues rather than the commonly assumed presence or absence of the highly aggregation-prone region of the NAC region of {alpha}-synuclein. This conclusion provides new insights into the role of {alpha}-synuclein in disease and into the factors that regulate the balance between solubility and aggregation of a natively unfolded protein.

Keywords: {alpha}-synuclein; β-synuclein; aggregation; NMR; protein engineering; fugu


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