Premium
Stabilization of discordant helices in amyloid fibril‐forming proteins
Author(s) -
Päiviö Anna,
Nordling Erik,
Kallberg Yvonne,
Thyberg Johan,
Johansson Jan
Publication year - 2004
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.03442404
Subject(s) - fibril , tripeptide , chemistry , peptide , biophysics , amyloid (mycology) , protein secondary structure , helix (gastropod) , protein structure , beta sheet , alpha helix , serine , crystallography , biochemistry , membrane , biology , phosphorylation , inorganic chemistry , ecology , snail
Several proteins and peptides that can convert from α‐helical to β‐sheet conformation and form amyloid fibrils, including the amyloid β‐peptide (Aβ) and the prion protein, contain a discordant α‐helix that is composed of residues that strongly favor β‐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 Aβ apparently lacks such interactions. The helical propensity of the Aβ discordant region (K 16 LVFFAED 23 ) 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 α‐helical content of Aβ(12–28) and reduces aggregation and fibril formation of Aβ(1–40), Aβ(12–28), Aβ(12–24), and Aβ(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 Aβ secondary structure or fibril formation. These data suggest that in free Aβ, the discordant α‐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.