Familial Alzheimer's disease mutations alter the stability of the amyloid beta-protein monomer folding nucleus.
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.
Grant
Marianne A
MA
Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Lazo
Noel D
ND
Lomakin
Aleksey
A
Condron
Margaret M
MM
Arai
Hiromi
H
Yamin
Ghiam
G
Rigby
Alan C
AC
Teplow
David B
DB
D000544:Alzheimer Disease / Q000235:genetics*; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D013058:Mass Spectrometry; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000737:chemistry* / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics; D017510:Protein Folding; D017433:Protein Structure, Secondary
D016229:Amyloid beta-Peptides; D009842:Oligopeptides; D010446:Peptide Fragments; C501831:amyloid beta-protein (21-30)