7JXN

Beta hairpin derived from Abeta17-36 with an F20Cha mutation

Summary for 7JXN

• Entry DOI: 10.2210/pdb7jxn/pdb
• Descriptor: Amyloid-beta 17-36 peptide, CHLORIDE ION, SODIUM ION, ... (4 entities in total)
• Functional Keywords: amyloid, oligomer, alzheimer's disease, beta-hairpin, de novo protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 8888.40

Authors

Kreutzer, A.G.,Haerianardakani, S.,Nowick, J.S. (deposition date: 2020-08-27, release date: 2020-12-09, Last modification date: 2025-04-02)

Primary citation

Haerianardakani, S.,Kreutzer, A.G.,Salveson, P.J.,Samdin, T.D.,Guaglianone, G.E.,Nowick, J.S.
Phenylalanine Mutation to Cyclohexylalanine Facilitates Triangular Trimer Formation by beta-Hairpins Derived from A beta.
J.Am.Chem.Soc., 142:20708-20716, 2020

PubMed Abstract: Oligomers of the β-amyloid peptide, Aβ, 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 Aβ oligomers. To gain insights into the structure and assembly of Aβ oligomers, our laboratory has previously designed and synthesized macrocyclic peptides derived from Aβ and Aβ that fold to form β-hairpins and assemble to form trimers. In this study, we found that mutating Phe to cyclohexylalanine (Cha) in macrocyclic Aβ-derived peptides promotes crystallization of an Aβ-derived peptide containing the Aβ loop (peptide ) and permits elucidation of its structure and assembly by X-ray crystallography. X-ray crystallography shows that peptide forms a hexamer. X-ray crystallography and SDS-PAGE further show that trimer , a covalently stabilized trimer derived from peptide , forms a dodecamer. Size exclusion chromatography shows that trimer forms higher-order assemblies in solution. Trimer exhibits cytotoxicity against the neuroblastoma cell line SH-SY5Y. These studies demonstrate the use of the F20Cha mutation to further stabilize oligomers of Aβ-derived peptides that contain more of the native sequence and thus better mimic the oligomers formed by full-length Aβ.

PubMed: 33237748
DOI: 10.1021/jacs.0c09281

Experimental method

X-RAY DIFFRACTION (2 Å)