Stabilization of discordant helices in amyloid fibril-forming proteins.
Several proteins and peptides that can convert from alpha-helical to beta-sheet conformation and form amyloid fibrils, including the amyloid beta-peptide (Abeta) 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 Abeta apparently lacks such interactions. The helical propensity of the Abeta 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 Abeta(12-28) and reduces aggregation and fibril formation of Abeta(1-40), Abeta(12-28), Abeta(12-24), and Abeta(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 Abeta secondary structure or fibril formation. These data suggest that in free Abeta, 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.
Päiviö
Anna
A
Department of Molecular Biosciences, Swedish University of Agricultural Sciences, The Biomedical Centre, S-751 23 Uppsala, Sweden.
Nordling
Erik
E
Kallberg
Yvonne
Y
Thyberg
Johan
J
Johansson
Jan
J
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry; D009943:Organophosphorus Compounds / Q000737:chemistry; D017433:Protein Structure, Secondary
D016229:Amyloid beta-Peptides; D009842:Oligopeptides; D009943:Organophosphorus Compounds