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Exploring the sequence determinants of amyloid structure using position-specific scoring matrices

A Corrigendum to this article was published on 29 September 2010

An Addendum to this article was published on 29 September 2010

This article has been updated

Abstract

Protein aggregation results in β-sheet–like assemblies that adopt either a variety of amorphous morphologies or ordered amyloid-like structures. These differences in structure also reflect biological differences; amyloid and amorphous β-sheet aggregates have different chaperone affinities, accumulate in different cellular locations and are degraded by different mechanisms. Further, amyloid function depends entirely on a high intrinsic degree of order. Here we experimentally explored the sequence space of amyloid hexapeptides and used the derived data to build Waltz, a web-based tool that uses a position-specific scoring matrix to determine amyloid-forming sequences. Waltz allows users to identify and better distinguish between amyloid sequences and amorphous β-sheet aggregates and allowed us to identify amyloid-forming regions in functional amyloids.

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Figure 1: Confirmation of cross-β structure.
Figure 2: Amino acid preference per position of the amyloid hexapeptide motif.
Figure 3: Specificity analysis of Waltz and Tango for amorphous aggregation and amyloid formation.
Figure 4: Cross-β-sheet diffraction pattern and structure.

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Change history

  • 29 September 2010

    In the original version of this Article published online, we had inadvertently neglected to provide a proper comparison to a tool that should have been shown in Table 1. We apologize for this oversight.

  • 29 September 2010

    In the version of this article initially published, the name of and reference to the algorithm in the right column of Table 1 was incorrect. The correct reference (ref. 40) has been added in the paper. The error has been corrected in the PDF and HTML versions of the article.

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Acknowledgements

S.M.-S. was supported by a Marie Curie Intraeuropean fellowship. I.C.M. was supported by a doctorate scholarship from the Boerhinger Ingelheim Fonds, Foundation for Basic Research in Biomedicine and then the Fundação para a Ciência e Tecnologia. L. Serpell acknowledges the grant support from the Alzheimer's Research Trust and the Biotechnology and Biological Sciences Research Council. L. Serrano was partly supported by the EC grant Apopis. J.W.H.S. and F.R. acknowledge grant support from the Federal Office for Scientific Affairs, Belgium (Interuniversity Attraction Pole P6/43), the Fund for Scientific Research, Flanders, the Institute for Innovation by Science & Technology Flanders, the Stichting Alzheimer Onderzoek and the Alzheimer's Research Trust.

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Authors

Contributions

S.M.-S., F.R., L. Serrano and J.S. devised the methods. S.M.-S. implemented software. J.R., S.M.-S., J.W.H.S. and F.R. performed analysis. M.D., N.K., M.L.d.I.P., I.C.M., K.L.M., A.C. and L. Serpell performed experiments. S.M.-S., J.S. and F.R. wrote the manuscript.

Corresponding authors

Correspondence to Luis Serrano, Joost W H Schymkowitz or Frederic Rousseau.

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The authors declare no competing financial interests.

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Supplementary Figures 1–3, Supplementary Tables 1–3 and Supplementary Notes 1–4 (PDF 1206 kb)

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Maurer-Stroh, S., Debulpaep, M., Kuemmerer, N. et al. Exploring the sequence determinants of amyloid structure using position-specific scoring matrices. Nat Methods 7, 237–242 (2010). https://doi.org/10.1038/nmeth.1432

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