Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Arrangement of subunits and ordering of β-strands in an amyloid sheet

Nature Structural Biology volume 9, pages 734–739 (2002)Cite this article

An Erratum to this article was published on 01 January 2003

Abstract

Amyloid fibrils are associated with several disease states, but their structures have yet to be fully defined. Here we use site-directed spin labeling to explain some of the specific interactions that are formed between subunits when the protein transthyretin (TTR) assembles into amyloid fibrils, which are associated with both spontaneous and familial amyloid diseases in humans. The results suggest that fibrils are formed when a major conformational change displaces the terminal β-strand from the edge of a β-sheet in the native structure, exposing the penultimate strand. The newly exposed strand then allows a novel β-sheet interaction to form between the TTR subunits. This interaction and another previously identified subunit association lead to a plausible model for the specific sequence of β-strands in one of the indefinitely repeating β-sheets of TTR amyloid, which is formed by a head-to-head, tail-to-tail arrangement of subunits.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The three-dimensional structure and self-assembly of transthyretin.
Figure 2: Site-directed spin labeling of B strand residues of TTR.
Figure 3: Site-directed spin labeling of C strand residues of TTR.
Figure 4: Arrangement of subunits and ordering of β-strands in TTR fibrils.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Sipe, J.D. Annu. Rev. Biochem. 61, 947–975 (1992).

    Article  CAS  Google Scholar 

  2. Perutz, M.F. Curr. Opin. Struct. Biol. 6, 848–858 (1996).

    Article  CAS  Google Scholar 

  3. Kelly, J.W. et al. Adv. Protein Chem. 50, 161–181 (1997).

    Article  CAS  Google Scholar 

  4. Sunde, M. et al. J. Mol. Biol. 273, 729–739 (1997).

    Article  CAS  Google Scholar 

  5. Westermark, P., Sletten, K., Johansson, B. & Cornwell, G.G. Proc. Natl. Acad. Sci. USA 87, 2843–2845 (1990).

    Article  CAS  Google Scholar 

  6. Kelly, J.W. Curr. Opin. Struct. Biol. 8, 101–106 (1998).

    Article  CAS  Google Scholar 

  7. Lai, Z., Colon, W. & Kelly, J.W. Biochemistry 35, 6470–6482 (1996).

    Article  CAS  Google Scholar 

  8. Lashuel, H.A., Lai, Z. & Kelly, J.W. Biochemistry 37, 17851–17864 (1998).

    Article  CAS  Google Scholar 

  9. Olofsson, A. et al. J. Biol. Chem. 276, 39592–39599 (2001).

    Article  CAS  Google Scholar 

  10. Serpell, L.C. et al. J. Mol. Biol. 254, 113–118 (1995).

    Article  CAS  Google Scholar 

  11. Serpell, L.C. et al. J Mol. Biol. 300, 1033–1039 (2000).

    Article  CAS  Google Scholar 

  12. Blake, C.C. & Serpell, L.C. Structure 4, 989–998 (1996).

    Article  CAS  Google Scholar 

  13. Serag, A.A., Altenbach, C., Gingery, M., Hubbell, W.L. & Yeates, T.O. Biochemistry 40, 9089–9096 (2001).

    Article  CAS  Google Scholar 

  14. Serpell, L.C., Goldsteins, G., Dacklin, I., Lundgren, E. & Blake, C.C. Amyloid 3, 75–85 (1996).

    Article  CAS  Google Scholar 

  15. Liu, K., Cho, H.S., Lashuel, H.A., Kelly, J.W. & Wemmer, D.E. Nature Struct. Biol. 7, 754–757 (2000).

    Article  CAS  Google Scholar 

  16. Eneqvist, T., Andersson, K., Olofsson, A., Lundgren, E. & Sauer-Eriksson, A.E. Mol. Cell 6, 1207–1218 (2000).

    Article  CAS  Google Scholar 

  17. Blake, C.C., Geisow, M.J., Oatley, S.J., Rerat, B. & Rerat, C. J. Mol. Biol. 121, 339–356 (1978).

    Article  CAS  Google Scholar 

  18. Eneqvist, T. & Sauer-Eriksson, A.E. Amyloid 8, 149–168 (2001).

    Article  CAS  Google Scholar 

  19. McParland, V.J., Kalverda, A.P., Homans, S.W. & Radford, S.E. Nature Struct. Biol. 9, 326–331 (2002).

    Article  CAS  Google Scholar 

  20. Hoshino, M. et al. Nature Struct. Biol. 9, 332–336 (2002).

    Article  CAS  Google Scholar 

  21. Liu, K. et al. J. Mol. Biol. 303, 555–655 (2000).

    Article  CAS  Google Scholar 

  22. Ekiel, I. & Abrahamson, M. J. Biol. Chem. 271, 1314–1321 (1996).

    Article  CAS  Google Scholar 

  23. Garzon-Rodriguez, W., Sepulveda-Becerra, M., Milton, S. & Glabe, C.G. J. Biol. Chem. 272, 21037–21044 (1997).

    Article  CAS  Google Scholar 

  24. Friedhoff, P., Schneider, A., Mandelkow, E.M. & Mandelkow, E. Biochemistry 37, 10223–10230 (1998).

    Article  CAS  Google Scholar 

  25. Enya, M. et al. Am. J. Pathol. 154, 271–279 (1999).

    Article  CAS  Google Scholar 

  26. Liu, Y., Gotte, G., Libonati, M. & Eisenberg, D. Nature Struct. Biol. 8, 211–214 (2001).

    Article  CAS  Google Scholar 

  27. Janowski, R. et al. Nature Struct. Biol. 8, 316–320 (2001).

    Article  CAS  Google Scholar 

  28. Knaus, K.J. et al. Nature Struct. Biol. 8, 770–774 (2001).

    Article  CAS  Google Scholar 

  29. Padilla, J.E., Colovos, C. & Yeates, T.O. Proc. Natl. Acad. Sci. USA 98, 2217–2221 (2001).

    Article  CAS  Google Scholar 

  30. Sunde, M. & Blake, C. Adv. Protein Chem. 50, 123–159 (1997).

    Article  CAS  Google Scholar 

  31. Rabenstein, M.D. & Shin, Y.K. Proc. Natl. Acad. Sci. USA 92, 8239–8243 (1995).

    Article  CAS  Google Scholar 

  32. Altenbach, C., Oh, K.J., Trabanino, R.J., Hideg, K. & Hubbell, W.L. Biochemistry 40, 15471–15482 (2001).

    Article  CAS  Google Scholar 

  33. Pake, G.E. J. Chem. Phys. 16, 327–336 (1948).

    Article  CAS  Google Scholar 

  34. Gross, A., Columbus, L., Hideg, K., Altenbach, C. & Hubbell, W.L. Biochemistry 38, 10324–10335 (1999).

    Article  CAS  Google Scholar 

  35. Richardson, J.S. & Richardson, D.C. Proc. Natl. Acad. Sci. USA 99, 2754–2759 (2002).

    Article  CAS  Google Scholar 

  36. Carson, M. Methods Enzymol. 277, 493–505 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank L. Columbus, D. Eisenberg, M. Phillips and M. Sawaya for helpful discussions and technical expertise. This work was supported by the NIH and the DOE-BER program. A.A.S. was supported in part by the Medical Scientist Training Program of the UCLA School of Medicine.

Author information

Authors and Affiliations

  1. Molecular Biology Institute and School of Medicine, University of California, Los Angeles, 90095, California, USA

    Ahmed A. Serag

  2. Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, 90095, California, USA

    Christian Altenbach & Wayne L. Hubbell

  3. Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, 90095, California, USA

    Mari Gingery

  4. Department of Chemistry and Biochemistry, and Department of Energy, Molecular Biology Institute, Laboratory of Structural Biology and Molecular Medicine, University of California, Los Angeles, 90095, California, USA

    Todd O. Yeates

Authors
  1. Ahmed A. Serag
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christian Altenbach
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mari Gingery
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wayne L. Hubbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Todd O. Yeates
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Todd O. Yeates.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Serag, A., Altenbach, C., Gingery, M. et al. Arrangement of subunits and ordering of β-strands in an amyloid sheet. Nat Struct Mol Biol 9, 734–739 (2002). https://doi.org/10.1038/nsb838

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsb838

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing