Structural highlights
Publication Abstract from PubMedThe 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 beta-amyloid peptide Abeta are especially important in the progression of Alzheimer's disease. In many Abeta oligomers, the Abeta monomer components are thought to adopt a beta-hairpin conformation. This paper describes the design and study of a macrocyclic beta-hairpin peptide derived from Abeta16-36. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and size exclusion chromatography studies show that the Abeta16-36 beta-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 Abeta16-36 beta-hairpin peptide are toxic toward neuronally derived SH-SY5Y cells. Replica-exchange molecular dynamics demonstrates that the hexamer can accommodate full-length Abeta. These findings expand our understanding of the structure, solution-phase behavior, and biological activity of Abeta oligomers and may offer insights into the molecular basis of Alzheimer's disease. A Hexamer of a Peptide Derived from Abeta16-36.,Kreutzer AG, Spencer RK, McKnelly KJ, Yoo S, Hamza IL, Salveson PJ, Nowick JS Biochemistry. 2017 Nov 14;56(45):6061-6071. doi: 10.1021/acs.biochem.7b00831., Epub 2017 Oct 27. PMID:29028351[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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