A simple algorithm locates β‐strands in the amyloid fibril core of α‐synuclein, Aβ, and tau using the amino acid sequence alone
- 1 May 2007
- journal article
- Published by Wiley in Protein Science
- Vol. 16 (5), 906-918
- https://doi.org/10.1110/ps.062624507
Abstract
Fibrillar inclusions are a characteristic feature of the neuropathology found in the alpha-synucleinopathies such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Familial forms of alpha-synucleinopathies have also been linked with missense mutations or gene multiplications that result in higher protein expression levels. In order to form these fibrils, the protein, alpha-synuclein (alpha-syn), must undergo a process of self-assembly in which its native state is converted from a disordered conformer into a beta-sheet-dominated form. Here, we have developed a novel polypeptide property calculator to locate and quantify relative propensities for beta-strand structure in the sequence of alpha-syn. The output of the algorithm, in the form of a simple x-y plot, was found to correlate very well with the location of the beta-sheet core in alpha-syn fibrils. In particular, the plot features three peaks, the largest of which is completely absent for the nonfibrillogenic protein, beta-syn. We also report similar significant correlations for the Alzheimer's disease-related proteins, Abeta and tau. A substantial region of alpha-syn is capable [corrected] of converting from its disordered conformation into a long [corrected] alpha-helical protein. We have developed the aforementioned algorithm to locate and quantify the alpha-helical hydrophobic moment in the amino acid sequence of alpha-syn. As before, the output of the algorithm, in the form of a simple x-y plot, was found to correlate very well with the location of alpha-helical structure in membrane bilayer-associated alpha-syn.Keywords
This publication has 114 references indexed in Scilit:
- 3D structure of Alzheimer's amyloid-β(1–42) fibrilsProceedings of the National Academy of Sciences, 2005
- Structure of the cross-β spine of amyloid-like fibrilsNature, 2005
- Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteinsNature Biotechnology, 2004
- Rationalization of the effects of mutations on peptide andprotein aggregation ratesNature, 2003
- A Structural and Functional Role for 11-mer Repeats in α-Synuclein and Other Exchangeable Lipid Binding ProteinsJournal of Molecular Biology, 2003
- Alpha-synuclein and neurodegenerative diseasesNature Reviews Neuroscience, 2001
- Conformational properties of α-synuclein in its free and lipid-associated states 1 1Edited by P. E. WrightJournal of Molecular Biology, 2001
- Fiber diffraction of synthetic α-synuclein filaments shows amyloid-like cross-β conformationProceedings of the National Academy of Sciences, 2000
- α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodiesProceedings of the National Academy of Sciences, 1998
- Stabilization of α-Synuclein Secondary Structure upon Binding to Synthetic MembranesJournal of Biological Chemistry, 1998