Amyloid formation from an α-helical peptide bundle is seeded by 310-helix aggregates

Singh, Yogendra, Sharpe, Philip C., Hoang, Huy N., Lucke, Andrew J., McDowall, Alasdair W., Bottomley, Stephen P. and Fairlie, David P. (2011) Amyloid formation from an α-helical peptide bundle is seeded by 310-helix aggregates. Chemistry: A European Journal, 17 1: 151-160.


Author Singh, Yogendra
Sharpe, Philip C.
Hoang, Huy N.
Lucke, Andrew J.
McDowall, Alasdair W.
Bottomley, Stephen P.
Fairlie, David P.
Title Amyloid formation from an α-helical peptide bundle is seeded by 310-helix aggregates
Formatted title Amyloid formation from an α-helical peptide bundle is seeded by 310-helix aggregates
Journal name Chemistry: A European Journal  (ERA 2012 Listed)    (ERA 2010 Rank A*)   Check publisher's open access policy
Publication date 2011-01-03
Sub-type Article
Year available 2010
DOI 10.1002/chem.201002500
Volume number 17
Issue number 1
ISSN 0947-6539; 1521-3765
Start page 151
End page 160
Total pages 10
Place of publication Weinheim, Germany
Publisher Wiley
Collection year 2012
Language eng
Formatted 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 310 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 310-helix aggregation triggered in this case by template-promoted helical bundling and by hydrogen-bonding glutamic acid side chains. A mechanism involving α⇌α4⇌(310)4⇌(310)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.
Keyword Aggregation
Amyloid
Beta sheets
Helical structures
Peptides
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article first published online: 15 DEC 2010

 
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Created: Wed, 21 Sep 2011, 00:07:46 EST by Dr Yogendra Singh on behalf of School of Chemistry & Molecular Biosciences