Lewandowski, Józef R., van der Wel, Patrick C. A., Rigney, Mike, Grigorieff, Nikolaus and Griffin, Robert G. (2011) Structural complexity of a composite amyloid fibril. Journal of the American Chemical Society, Vol.133 (No.37). pp. 14686-14698. doi:10.1021/ja203736z ISSN 0002-7863.

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Abstract

The molecular structure of amyloid fibrils and the mechanism of their formation are of substantial medical and biological importance, but present an ongoing experimental and computational challenge. An early high-resolution view of amyloid-like structure was obtained on amyloid-like crystals of a small fragment of the yeast prion protein Sup35p: the peptide GNNQQNY. As GNNQQNY also forms amyloid-like fibrils under similar conditions, it has been theorized that the crystal's structural features are shared by the fibrils. Here we apply magic-angle-spinning (MAS) NMR to examine the structure and dynamics of these fibrils. Previously multiple NMR signals were observed for such samples, seemingly consistent with the presence of polymorphic fibrils. Here we demonstrate that peptides with these three distinct conformations instead assemble together into composite protofilaments. Electron microscopy (EM) of the ribbon-like fibrils indicates that these protofilaments combine in differing ways to form striations of variable widths, presenting another level of structural complexity. Structural and dynamic NMR data reveal the presence of highly restricted side-chain conformations involved in interfaces between differently structured peptides, likely comprising interdigitated steric zippers. We outline molecular interfaces that are consistent with the observed EM and NMR data. The rigid and uniform structure of the GNNQQNY crystals is found to contrast distinctly with the more complex structural and dynamic nature of these "composite" amyloid fibrils. These results provide insight into the fibril-crystal distinction and also indicate a necessary caution with respect to the extrapolation of crystal structures to the study of fibril structure and formation.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry
Divisions:	Faculty of Science, Engineering and Medicine > Science > Chemistry
Library of Congress Subject Headings (LCSH):	Amyloid beta-protein -- Structure, Nuclear magnetic resonance spectroscopy
Journal or Publication Title:	Journal of the American Chemical Society
Publisher:	American Chemical Society
ISSN:	0002-7863
Official Date:	21 September 2011
Dates:	Date Event 21 September 2011 Published
Volume:	Vol.133
Number:	No.37
Page Range:	pp. 14686-14698
DOI:	10.1021/ja203736z
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	National Institutes of Health (U.S.) (NIH)
Grant number:	P41 RR-01081 (NIH), EB-003151 (NIH), EB-002026 (NIH)

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