Rivers, R.C. and Kumita, J.R. and Tartaglia, G.G. and Dedmon, M.M. and Pawar, A. and Vendruscolo, M. and Dobson, C.M. and Christodoulou, John (2009) Molecular determinants of the aggregation behavior of α- and β-synuclein. Protein Science 17 (5), pp. 887-898. ISSN 0961-8368.
Abstract
α- 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 α- 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 α-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 α-synuclein. This conclusion provides new insights into the role of α-synuclein in disease and into the factors that regulate the balance between solubility and aggregation of a natively unfolded protein.
Metadata
| Item Type: | Article |
|---|---|
| Keyword(s) / Subject(s): | α-synuclein, β-synuclein, aggregation, NMR, protein engineering, fugu |
| School: | Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences |
| Research Centres and Institutes: | Structural Molecular Biology, Institute of (ISMB) |
| Depositing User: | Administrator |
| Date Deposited: | 20 May 2013 12:00 |
| Last Modified: | 02 Aug 2023 17:04 |
| URI: | https://eprints.bbk.ac.uk/id/eprint/6887 |
Statistics
Additional statistics are available via IRStats2.
Archive Staff Only (login required)
