A Hexamer of a Peptide Derived from A?16-36.

ABSTRACT: 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 ?-amyloid peptide A? are especially important in the progression of Alzheimer's disease. In many A? oligomers, the A? monomer components are thought to adopt a ?-hairpin conformation. This paper describes the design and study of a macrocyclic ?-hairpin peptide derived from A?16-36. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and size exclusion chromatography studies show that the A?16-36 ?-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 A?16-36 ?-hairpin peptide are toxic toward neuronally derived SH-SY5Y cells. Replica-exchange molecular dynamics demonstrates that the hexamer can accommodate full-length A?. These findings expand our understanding of the structure, solution-phase behavior, and biological activity of A? oligomers and may offer insights into the molecular basis of Alzheimer's disease.

SUBMITTER: Kreutzer AG 

PROVIDER: S-EPMC5689071 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature