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

  • Author(s): Grant, Marianne A
  • Lazo, Noel D
  • Lomakin, Aleksey
  • Condron, Margaret M
  • Arai, Hiromi
  • Yamin, Ghiam
  • Rigby, Alan C
  • Teplow, David B
  • et al.

Published Web Location

https://doi.org/10.1073/pnas.0705197104
No data is associated with this publication.
Abstract

Amyloid beta-protein (Abeta) oligomers may be the proximate neurotoxins in Alzheimer's disease (AD). Recently, to elucidate the oligomerization pathway, we studied Abeta monomer folding and identified a decapeptide segment of Abeta, (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 Abeta(21-30) turn within wild-type Abeta and seven clinically relevant homologues. In addition, we determined the relative differences in folding free energies (DeltaDeltaG(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 Abeta monomer folding and disease causation are discussed.

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Familial_Alzheimer_s_disease_mutations_alter_the_stability_of_the_amyloid__-protein_monomer_folding_nucleus.pdf

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