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Amyloid Formation from an α-Helix Peptide Bundle Is Seeded by 3_(10-)Helix Aggregates

Singh, Yogendra and Sharpe, Philip C. and Hoang, Huy N. and Lucke, Andrew J. and McDowall, Alasdair W. and Bottomley, Stephen P. and Fairlie, David P. (2011) Amyloid Formation from an α-Helix Peptide Bundle Is Seeded by 3_(10-)Helix Aggregates. Chemistry-A European Journal, 17 (1). pp. 151-160. ISSN 0947-6539. http://resolver.caltech.edu/CaltechAUTHORS:20110303-151649002

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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.


Item Type:Article
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http://dx.doi.org/10.1002/chem.201002500DOIUNSPECIFIED
http://onlinelibrary.wiley.com/doi/10.1002/chem.201002500/fullPublisherUNSPECIFIED
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.
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Funding AgencyGrant Number
Australian Research Council (ARC)UNSPECIFIED
Australian National Health and Medical Research Council (NHMRC)UNSPECIFIED
Subject Keywords:aggregation; amyloid; beta sheets; helical structures; peptides
Record Number:CaltechAUTHORS:20110303-151649002
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20110303-151649002
Official Citation:Amyloid Formation from an α-Helix Peptide Bundle Is Seeded by 310-Helix Aggregates Dr. Yogendra Singh1, Dr. Philip C. Sharpe1, Dr. Huy N. Hoang1, Dr. Andrew J. Lucke1, Dr. Alasdair W. McDowall2, Prof. Stephen P. Bottomley3, Prof. David P. Fairlie1,*Article first published online: 15 DEC 2010 DOI: 10.1002/chem.201002500
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:22648
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:03 Mar 2011 23:55
Last Modified:23 Aug 2016 09:59

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