Familial Alzheimer's disease mutations alter the stability of the amyloid β-protein monomer folding nucleus

• DOI: 10.1073/pnas.0705197104
• Publication Date: 2007-10-11T01:10:20Z
• Authors: Marianne A. Grant; Noel D. Lazo; Aleksey Lomakin; Margaret M. Condron; Hiromi Arai; Ghiam Yamin; Alan C. Rigby; David B. Teplow
• Keywords: 0301 basic medicine; Protein Folding; Amyloid beta-Peptides; Mass Spectrometry; Peptide Fragments; Protein Structure, Secondary; 3. Good health; 03 medical and health sciences; Amino Acid Substitution; Alzheimer Disease; Mutation; Humans; Nuclear Magnetic Resonance, Biomolecular; Oligopeptides

Amyloid β-protein (Aβ) oligomers may be the proximate neurotoxins in Alzheimer's disease (AD). Recently, to elucidate the oligomerization pathway, we studied Aβ monomer folding and identified a decapeptide segment of Aβ, 21 Ala– 22 Glu– 23 Asp– 24 Val– 25 Gly– 26 Ser– 27 Asn– 28 Lys– 29 Gly– 30 Ala, within which turn formation appears to nucleate monomer folding. The turn is stabilized by hydrophobic interactions between Val-24 and Lys-28 and by long-range electrostatic interactions between Lys-28 and either Glu-22 or Asp-23. We hypothesized that turn destabilization might explain the effects of amino acid substitutions at Glu-22 and Asp-23 that cause familial forms of AD and cerebral amyloid angiopathy. To test this hypothesis, limited proteolysis, mass spectrometry, and solution-state NMR spectroscopy were used here to determine and compare the structure and stability of the Aβ(21–30) turn within wild-type Aβ and seven clinically relevant homologues. In addition, we determined the relative differences in folding free energies (ΔΔ G f ) among the mutant peptides. We observed that all of the disease-associated amino acid substitutions at Glu-22 or Asp-23 destabilized the turn and that the magnitude of the destabilization correlated with oligomerization propensity. The Ala21Gly (Flemish) substitution, outside the turn proper (Glu-22–Lys-28), displayed a stability similar to that of the wild-type peptide. The implications of these findings for understanding Aβ monomer folding and disease causation are discussed.