8t89

Publication Abstract from PubMed

The rippled beta-sheet was theorized by Pauling and Corey in 1953 as a structural motif in which mirror image peptide strands assemble into hydrogen-bonded periodic arrays with strictly alternating chirality. Structural characterization of the rippled beta-sheet was limited to biophysical methods until 2022 when atomic resolution structures of the motif were first obtained. The crystal structural foundation is restricted to four model tripeptides composed exclusively of aromatic residues. Here, we report five new rippled sheet crystal structures derived from amyloid beta and amylin, the aggregating toxic peptides of Alzheimer's disease and type II diabetes, respectively. Despite the variation in peptide sequence composition, all five structures form antiparallel rippled beta-sheets that extend, like a fibril, along the entire length of the crystalline needle. The long-range packing of the crystals, however, varies. In three of the crystals, the sheets pack face-to-face and exclude water, giving rise to cross-beta architectures grossly resembling the steric zipper motif of amyloid fibrils but differing in fundamental details. In the other two crystals, the solvent is encapsulated between the sheets, yielding fibril architectures capable of host-guest chemistry. Our study demonstrates that the formation of rippled beta-sheets from aggregating racemic peptide mixtures in three-dimensional (3D) assemblies is a general phenomenon and provides a structural basis for targeting intrinsically disordered proteins.

Racemic Peptides from Amyloid beta and Amylin Form Rippled beta-Sheets Rather Than Pleated beta-Sheets.,Hazari A, Sawaya MR, Sajimon M, Vlahakis N, Rodriguez J, Eisenberg D, Raskatov JA J Am Chem Soc. 2023 Nov 29;145(47):25917-25926. doi: 10.1021/jacs.3c11712. Epub , 2023 Nov 16. PMID:37972334^[1]

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