A Hexamer of a Peptide Derived from Aβ<sub>16–36</sub>
Adam G. Kreutzer
Ryan K. Spencer
Kate J. McKnelly
Stan Yoo
Imane L. Hamza
Patrick J. Salveson
James S. Nowick
10.1021/acs.biochem.7b00831.s001
https://acs.figshare.com/articles/journal_contribution/A_Hexamer_of_a_Peptide_Derived_from_A_sub_16_36_sub_/5545414
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 Aβ<sub>16–36</sub>. Sodium dodecyl sulfate–polyacrylamide
gel electrophoresis and size exclusion chromatography studies show
that the Aβ<sub>16–36</sub> 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
Aβ<sub>16–36</sub> 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.
2017-10-13 00:00:00
macrocyclic β- hairpin peptide
β- hairpin conformation
dimers
hexamer
size exclusion chromatography studies show
β oligomers
Alzheimer
SH-SY 5Y cells
understanding
trimer
β monomer components
β- amyloid peptide
Lactate dehydrogenase release assays show