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Effects of N-Terminal Residues on the Assembly of Constrained β-Hairpin Peptides Derived from Aβ. | LitMetric

AI Article Synopsis

Article Abstract

This paper describes the synthesis, solution-phase biophysical studies, and X-ray crystallographic structures of hexamers formed by macrocyclic β-hairpin peptides derived from the central and C-terminal regions of Aβ, which bear "tails" derived from the N-terminus of Aβ. Soluble oligomers of the β-amyloid peptide, Aβ, are thought to be the synaptotoxic species responsible for neurodegeneration in Alzheimer's disease. Over the last 20 years, evidence has accumulated that implicates the N-terminus of Aβ as a region that may initiate the formation of damaging oligomeric species. We previously studied, in our laboratory, macrocyclic β-hairpin peptides derived from Aβ and Aβ, capable of forming hexamers that can be observed by X-ray crystallography and SDS-PAGE. To better mimic oligomers of full length Aβ, we use an orthogonal protecting group strategy during the synthesis to append residues from Aβ to the parent macrocyclic β-hairpin peptide , which comprises Aβ and Aβ. The N-terminally extended peptides , , , , , , , and assemble to form dimers, trimers, and hexamers in solution-phase studies. X-ray crystallography reveals that peptide assembles to form a hexamer that is composed of dimers and trimers. These observations are consistent with a model in which the assembly of Aβ oligomers is driven by hydrogen bonding and hydrophobic packing of the residues from the central and C-terminal regions, with the N-terminus of Aβ accommodated by the oligomers as an unstructured tail.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927569PMC
http://dx.doi.org/10.1021/jacs.0c05186DOI Listing

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