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

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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.

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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.

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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.

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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

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  1. Ahmed A. Serag
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  2. Christian Altenbach
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  3. Mari Gingery
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  4. Wayne L. Hubbell
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  5. Todd O. Yeates
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Correspondence to Todd O. Yeates.

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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

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