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Publication Abstract from PubMed

Oligomers of the beta-amyloid peptide, Abeta, play a central role in the pathogenesis and progression of Alzheimer's disease. Trimers and higher-order oligomers composed of trimers are thought to be the most neurotoxic Abeta oligomers. To gain insights into the structure and assembly of Abeta oligomers, our laboratory has previously designed and synthesized macrocyclic peptides derived from Abeta17-23 and Abeta30-36 that fold to form beta-hairpins and assemble to form trimers. In this study, we found that mutating Phe20 to cyclohexylalanine (Cha) in macrocyclic Abeta-derived peptides promotes crystallization of an Abeta-derived peptide containing the Abeta24-29 loop (peptide 3F20Cha) and permits elucidation of its structure and assembly by X-ray crystallography. X-ray crystallography shows that peptide 3F20Cha forms a hexamer. X-ray crystallography and SDS-PAGE further show that trimer 4F20Cha, a covalently stabilized trimer derived from peptide 3F20Cha, forms a dodecamer. Size exclusion chromatography shows that trimer 4F20Cha forms higher-order assemblies in solution. Trimer 4F20Cha exhibits cytotoxicity against the neuroblastoma cell line SH-SY5Y. These studies demonstrate the use of the F20Cha mutation to further stabilize oligomers of Abeta-derived peptides that contain more of the native sequence and thus better mimic the oligomers formed by full-length Abeta.

Phenylalanine Mutation to Cyclohexylalanine Facilitates Triangular Trimer Formation by beta-Hairpins Derived from Abeta.,Haerianardakani S, Kreutzer AG, Salveson PJ, Samdin TD, Guaglianone GE, Nowick JS J Am Chem Soc. 2020 Nov 25. doi: 10.1021/jacs.0c09281. PMID:33237748^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.