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A de novo designed helix-turn-helix peptide forms nontoxic amyloid fibrils

Nature Structural Biology volume 7, pages 1095–1099 (2000)Cite this article

Abstract

We report here that a monomeric de novo designed α-helix-turn-α-helix peptide, αtα, when incubated at 37 °C in an aqueous buffer at neutral pH, forms nonbranching, protease resistant fibrils that are 6–10 nm in diameter. These fibrils are rich in β-sheet and bind the amyloidophilic dye Congo red. αtα fibrils thus display the morphologic, structural, and tinctorial properties of authentic amyloid fibrils. Surprisingly, unlike fibrils formed by peptides such as the amyloid β-protein or the islet amyloid polypeptide, αtα fibrils were not toxic to cultured rat primary cortical neurons or PC12 cells. These results suggest that the potential to form fibrils under physiologic conditions is not limited to those proteins associated with amyloidoses and that fibril formation alone is not predictive of cytotoxic activity.

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Figure 1: Fibril formation by αtα.
Figure 2: Conformational stability of αtα.
Figure 3: Stereo view of αtα showing the charged residues located near the hydrophobic interface.
Figure 4: Temporal changes in the secondary structure of αtα during fibrillogenesis.
Figure 5: Effect of amyloid peptides on MTT formazan formation by PC12 cells.

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Acknowledgements

We thank C. Lemere for assistance with the birefringence experiment, A. Bissello for performing mass spectroscopy, S. Vasquez for preparation of primary neuronal cultures, and M. Condron for peptide synthesis and amino acid analysis. This work was supported by grants from the National Institutes of Health (D.B.T., D.J.S., and Y.F.), and by the Foundation for Neurologic Diseases (D.B.T and D.J.S.).

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Authors and Affiliations

  1. Department of Neurology (Neuroscience), Harvard Medical School, and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, 02115, Massachusetts, USA

    Youcef Fezoui, Dean M. Hartley, Dominic M. Walsh, Dennis J. Selkoe & David B. Teplow

  2. Rowland Institute for Science, Cambridge , 02142, Massachusetts, USA

    John J. Osterhout

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  1. Youcef Fezoui
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  2. Dean M. Hartley
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  6. David B. Teplow
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Correspondence to Youcef Fezoui or David B. Teplow.

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Fezoui, Y., Hartley, D., Walsh, D. et al. A de novo designed helix-turn-helix peptide forms nontoxic amyloid fibrils. Nat Struct Mol Biol 7, 1095–1099 (2000). https://doi.org/10.1038/81937

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