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Protein Science (2004), 13:1251-1259. Published by Cold Spring Harbor Laboratory Press. Copyright © 2004 The Protein Society
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Stabilization of discordant helices in amyloid fibril-forming proteins

Anna Päiviö1, Erik Nordling2, Yvonne Kallberg2, Johan Thyberg3 and Jan Johansson1

1 Department of Molecular Biosciences, Swedish University of Agricultural Sciences, The Biomedical Centre, S-751 23 Uppsala, Sweden
2 Department of Medical Biochemistry and Biophysics and
3 Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, S-171 77 Stockholm, Sweden

(RECEIVED September 17, 2003; FINAL REVISION December 2, 2003; ACCEPTED January 20, 2004)



Abstract

Several proteins and peptides that can convert from {alpha}-helical to {beta}-sheet conformation and form amyloid fibrils, including the amyloid {beta}-peptide (A{beta}) and the prion protein, contain a discordant {alpha}-helix that is composed of residues that strongly favor {beta}-strand formation. In their native states, 37 of 38 discordant helices are now found to interact with other protein segments or with lipid membranes, but A{beta} apparently lacks such interactions. The helical propensity of the A{beta} discordant region (K16LVFFAED23) is increased by introducing V18A/F19A/F20A replacements, and this is associated with reduced fibril formation. Addition of the tripeptide KAD or phospho-L-serine likewise increases the {alpha}-helical content of A{beta}(12–28) and reduces aggregation and fibril formation of A{beta}(1–40), A{beta}(12–28), A{beta}(12–24), and A{beta}(14–23). In contrast, tripeptides with all-neutral, all-acidic or all-basic side chains, as well as phosphoethanolamine, phosphocholine, and phosphoglycerol have no significant effects on A{beta} secondary structure or fibril formation. These data suggest that in free A{beta}, the discordant {alpha}-helix lacks stabilizing interactions (likely as a consequence of proteolytic removal from a membrane-associated precursor protein) and that stabilization of this helix can reduce fibril formation.

Abbreviations: A{beta}, amyloid {beta}-peptide • AD, Alzheimer’s disease • APP, amyloid precursor protein • ASA, accessible surface area • CD, circular dichroism • PrP, prion protein • TFE, trifluoroethanol • ThT, thioflavin T

Keywords: {alpha}-helix; protein structure; protein aggregation; conformational disease

Reprint requests to: Jan Johansson, Department of Molecular Biosciences, Swedish University of Agricultural Sciences, The Biomedical Centre, Box 575, S-751 23 Uppsala, Sweden; e-mail: jan.johansson{at}vmk.slu.se; fax: 46-18-550762.

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03442404.


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