Display Settings:

Format

Send to:

Choose Destination
Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16522-7. Epub 2007 Oct 10.

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

Author information

  • 1Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.

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.

PMID:
17940047
[PubMed - indexed for MEDLINE]
PMCID:
PMC2034231
Free PMC Article

Images from this publication.See all images (4)Free text

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk