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A simple algorithm locates -strands in the amyloid fibril core of -synuclein, A, and tau using the amino acid sequence alone

¹ Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom
² MRC Laboratory of Molecular Biology, Cambridge, Cambridge CB2 2QH, United Kingdom

(RECEIVED October 24, 2006; FINAL REVISION February 8, 2007; ACCEPTED February 18, 2007)

Fibrillar inclusions are a characteristic feature of the neuropathology found in the -synucleinopathies such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Familial forms of -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, -synuclein (-syn), must undergo a process of self-assembly in which its native state is converted from a disordered conformer into a -sheet-dominated form. Here, we have developed a novel polypeptide property calculator to locate and quantify relative propensities for -strand structure in the sequence of -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 -sheet core in -syn fibrils. In particular, the plot features three peaks, the largest of which is completely absent for the nonfibrillogenic protein, -syn. We also report similar significant correlations for the Alzheimer's disease-related proteins, A and tau. A substantial region of -syn is also of converting from its disordered conformation into a long amphipathic -helical protein. We have developed the aforementioned algorithm to locate and quantify the -helical hydrophobic moment in the amino acid sequence of -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 -helical structure in membrane bilayer-associated -syn.

Keywords: -synuclein; -strand propensity; Alzheimer's disease; Parkinson's disease; algorithm; amyloid fibril

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