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Publication Abstract from PubMed

Amyloid-beta (Abeta) forms heterogeneous oligomers, which are implicated in the pathogenesis of Alzheimer's disease (AD). Many Abeta oligomers consist of beta-hairpin building blocks horizontal line Abeta peptides in beta-hairpin conformations. beta-Hairpins of Abeta can adopt a variety of alignments, but the role that beta-hairpin alignment plays in the formation and heterogeneity of Abeta oligomers is poorly understood. To explore the effect of beta-hairpin alignment on the oligomerization of Abeta peptides, we designed and studied two model peptides with two different beta-hairpin alignments. Peptides Abetam(17-36) and Abetam(17-35) mimic two different beta-hairpins that Abeta can form, the Abeta(17-36) and Abeta(17-35) beta-hairpins, respectively. These hairpins are similar in composition but differ in hairpin alignment, altering the facial arrangements of the side chains of the residues that they contain. X-ray crystallography and SDS-PAGE demonstrate that the difference in facial arrangement between these peptides leads to distinct oligomer formation. In the crystal state, Abetam(17-36) forms triangular trimers that further assemble to form hexamers, while Abetam(17-35) forms tetrameric beta-barrels. In SDS-PAGE, Abetam(17-36) assembles to form a ladder of oligomers, while Abetam(17-35) either assembles to form a dimer or does not assemble at all. The differences in the behavior of Abetam(17-36) and Abetam(17-35) suggest beta-hairpin alignment as a source of the observed heterogeneity of Abeta oligomers.

beta-Hairpin Alignment Alters Oligomer Formation in Abeta-Derived Peptides.,Ruttenberg SM, Kreutzer AG, Truex NL, Nowick JS Biochemistry. 2024 Jan 16;63(2):212-218. doi: 10.1021/acs.biochem.3c00526. Epub , 2024 Jan 1. PMID:38163326^[1]

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