Amyloid formation from an alpha-helix peptide bundle is seeded by 3(10)-helix aggregates

Yogendra Singh, Philip C Sharpe, Huy N Hoang, Andrew J Lucke, Alasdair McDowall, Stephen P Bottomley, David P Fairlie

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21 Citations (Scopus)

Abstract

Transformation of proteins and peptides to fibrillar aggregates rich in beta sheets underlies many diseases, but mechanistic details of these structural transitions are poorly understood. To simulate aggregation, four equivalents of a water-soluble, alpha-helical (65 ) amphipathic peptide (AEQLLQEAEQLLQEL) were assembled in parallel on an oxazole-containing macrocyclic scaffold. The resulting 4alpha-helix bundle is monomeric and even more alpha helical (85 ), but it is also unstable at pH 4 and undergoes concentration-dependent conversion to beta-sheet aggregates and amyloid fibrils. Fibrils twist and grow with time, remaining flexible like rope (>1 mum long, 5-50 nm wide) with multiple strings (2 nm), before ageing to matted fibers. At pH 7 the fibrils revert back to soluble monomeric 4alpha-helix bundles. During alpha-->beta folding we were able to detect soluble 3(10) helices in solution by using 2D-NMR, CD and FTIR spectroscopy. This intermediate satisfies the need for peptide elongation, from the compressed alpha helix to the fully extended beta strand/sheet, and is driven here by 3(10) -helix aggregation triggered in this case by template-promoted helical bundling and by hydrogen-bonding glutamic acid side chains. A mechanism involving alpharight harpoon over left harpoonalpha(4) right harpoon over left harpoon(3(10) )(4) right harpoon over left harpoon(3(10) )(n) right harpoon over left harpoon(beta)(n) left harpoon over right harpoonm(beta)(n) equilibria is plausible for this peptide and also for peptides lacking hydrogen-bonding side chains, with unfavourable equilibria slowing the alpha-->beta conversion.
Original languageEnglish
Pages (from-to)151 - 160
Number of pages10
JournalChemistry - A European Journal
Volume17
Issue number1
DOIs
Publication statusPublished - 2011

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