High-resolution structures of oligomers
formed by the β-amyloid
peptide Aβ are needed to understand the molecular basis of Alzheimer’s
disease and develop therapies. This paper presents the X-ray crystallographic
structures of oligomers formed by a 20-residue peptide segment derived
from Aβ. The development of a peptide in which Aβ17–36 is stabilized as a β-hairpin is described,
and the X-ray crystallographic structures of oligomers it forms are
reported. Two covalent constraints act in tandem to stabilize the
Aβ17–36 peptide in a hairpin conformation:
a δ-linked ornithine turn connecting positions 17 and 36 to
create a macrocycle and an intramolecular disulfide linkage between
positions 24 and 29. An N-methyl group at position
33 blocks uncontrolled aggregation. The peptide readily crystallizes
as a folded β-hairpin, which assembles hierarchically in the
crystal lattice. Three β-hairpin monomers assemble to form a
triangular trimer, four trimers assemble in a tetrahedral arrangement
to form a dodecamer, and five dodecamers pack together to form an
annular pore. This hierarchical assembly provides a model, in which
full-length Aβ transitions from an unfolded monomer to a folded
β-hairpin, which assembles to form oligomers that further pack
to form an annular pore. This model may provide a better understanding
of the molecular basis of Alzheimer’s disease at atomic resolution.
The absence of high-resolution
structures of amyloid oligomers
constitutes a major gap in our understanding of amyloid diseases.
A growing body of evidence indicates that oligomers of the β-amyloid
peptide Aβ are especially important in the progression of Alzheimer’s
disease. In many Aβ oligomers, the Aβ monomer components
are thought to adopt a β-hairpin conformation. This paper describes
the design and study of a macrocyclic β-hairpin peptide derived
from Aβ16–36. Sodium dodecyl sulfate–polyacrylamide
gel electrophoresis and size exclusion chromatography studies show
that the Aβ16–36 β-hairpin peptide assembles
in solution to form hexamers, trimers, and dimers. X-ray crystallography
reveals that the peptide assembles to form a hexamer in the crystal
state and that the hexamer is composed of dimers and trimers. Lactate
dehydrogenase release assays show that the oligomers formed by the
Aβ16–36 β-hairpin peptide are toxic
toward neuronally derived SH-SY5Y cells. Replica-exchange molecular
dynamics demonstrates that the hexamer can accommodate full-length
Aβ. These findings expand our understanding of the structure,
solution-phase behavior, and biological activity of Aβ oligomers
and may offer insights into the molecular basis of Alzheimer’s
disease.
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