Amyloid Formation from an α-Helix Peptide Bundle Is Seeded by 3_(10-)Helix Aggregates
Abstract
Transformation of proteins and peptides to fibrillar aggregates rich in β sheets underlies many diseases, but mechanistic details of these structural transitions are poorly understood. To simulate aggregation, four equivalents of a water-soluble, α-helical (65 %) amphipathic peptide (AEQLLQEAEQLLQEL) were assembled in parallel on an oxazole-containing macrocyclic scaffold. The resulting 4α-helix bundle is monomeric and even more α helical (85 %), but it is also unstable at pH 4 and undergoes concentration-dependent conversion to β-sheet aggregates and amyloid fibrils. Fibrils twist and grow with time, remaining flexible like rope (>1 μm 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 4α-helix bundles. During α→β 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 α helix to the fully extended β 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 α⇌α_4⇌(3_(10))4⇌(3_(10))n⇌(β)_n⇋m(β)_n equilibria is plausible for this peptide and also for peptides lacking hydrogen-bonding side chains, with unfavourable equilibria slowing the α→β conversion.
Additional Information
© 2011 Wiley-VCH Verlag. Received: August 30, 2010. Article first published online: 15 Dec 2010. We thank the Australian Research Council (ARC) and the Australian National Health and Medical Research Council (NHMRC) for partial funding of this work and the ARC for a Federation Fellowship to D.P.F.Additional details
- Eprint ID
- 22648
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- CaltechAUTHORS:20110303-151649002
- Australian Research Council (ARC)
- Australian National Health and Medical Research Council (NHMRC)
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2011-03-03Created from EPrint's datestamp field
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2021-11-09Created from EPrint's last_modified field