3 years ago

A Hexamer of a Peptide Derived from Aβ16–36

A Hexamer of a Peptide Derived from Aβ16–36
James S. Nowick, Stan Yoo, Imane L. Hamza, Patrick J. Salveson, Ryan K. Spencer, Kate J. McKnelly, Adam G. Kreutzer
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.

Publisher URL: http://dx.doi.org/10.1021/acs.biochem.7b00831

DOI: 10.1021/acs.biochem.7b00831

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