Protein Engineering, Vol 11, 761-767, Copyright © 1998 by Oxford University Press
MO Chaney, SD Webster, YM Kuo and AE Roher
The three-dimensional structure of the Alzheimer's disease Abeta1-42
peptide was predicted by sequence homology, threading approaches and by
experimental observations. The Abeta molecule displayed a Greek key motif
with four antiparallel beta-strands. To shield thermodynamically
unfavorable domains, two Abeta molecules interact with each other to
generate a beta-barrel structure with a hydrophilic surface and a
hydrophobic core. The N-terminal domains of the dimer form crevices into
which the non-polar C-termini are accommodated to yield a globular
structure 27x32 A in diameter. Alternatively, the C-terminal domains of two
opposing dimers could be extended to form an antiparallel beta- sheet. The
stacking of these building blocks generates a helical protofilament. To
create a thermodynamically more favorable structure, three protofilaments
associate into a right-handed triple helix with a hydrophobic beta-sheet
completely surrounded by the hydrophilic beta- barrels made of residues
1-28. Two triple helical strands can further associate into a right-handed
amyloid filament. Although our model did not meet all the expected
criteria, it nevertheless exhibited a series of naturally disposed
structural features, revealed by other biophysical studies utilizing
synthetic Abeta peptides. These characteristics are of functional
significance in terms of Abeta- topology, fibril formation and
cytotoxicity. The model also suggests that Abeta may not exist in a
thermodynamically stable conformation, but rather as an ensemble of
metastable dimeric structures some of which are capable of generating an
extended C-terminal antiparallel beta-sheet essential in the promotion of
fibrillogenesis.
ARTICLES
Molecular modeling of the Abeta1-42 peptide from Alzheimer's disease
Biotechnology Core, Eli Lilly Research Laboratories, Indianapolis, IN 46285, USA.
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