Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 42, Pages 16522-16527Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0705197104
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Funding
- NIA NIH HHS [P01 AG027818, AG027818] Funding Source: Medline
- NINDS NIH HHS [R01 NS038328, NS038328] Funding Source: Medline
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Amyloid P-protein (A beta) oligomers may be the proximate neurotoxins in Alzheimer's disease (AD). Recently, to elucidate the oligonnerization pathway, we studied AP monomer folding and identified a decapepticle segment of A beta, (21)Ala-(22)Glu-(23)Asp-(24)Val(25)G ly-(26)Ser-(27)Asn-(28)LyS-(29)Gly-(30)AIa, within which turn formation appears to nucleate monomer folding. The turn is stabilized by hydrophobic interactions between Val-24 and Lys-28 and by longrange 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 A beta(21-30) turn within wild-type A beta and seven clinically relevant homologues. In addition, we determined the relative differences in folding free energies (Delta Delta G(f)) among the mutant pepticles. 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 oligonnerization propensity. The Ala21Gly (Flemish) substitution, outside the turn proper (Glu-22-Lys-28), displayed a stability similar to that of the wild-type pepticle. The implications of these findings for understanding A beta monomer folding and disease causation are discussed.
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