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Designed peptides that assemble into cross-α amyloid-like structures

Nature Chemical Biology volume 14, pages 870–875 (2018)Cite this article

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Abstract

Amyloids adopt ‘cross-β’ structures composed of long, twisted fibrils with β-strands running perpendicular to the fibril axis. Recently, a toxic peptide was proposed to form amyloid-like cross-α structures in solution, with a planar bilayer-like assembly observed in the crystal structure. Here we crystallographically characterize designed peptides that assemble into spiraling cross-α amyloid-like structures, which resemble twisted β-amyloid fibrils. The peptides form helical dimers, stabilized by packing of small and apolar residues, and the dimers further assemble into cross-α amyloid-like fibrils with superhelical pitches ranging from 170 Å to 200 Å. When a small residue that appeared critical for packing was converted to leucine, it resulted in structural rearrangement to a helical polymer. Fluorescently tagged versions of the designed peptides form puncta in mammalian cells, which recover from photobleaching with markedly different kinetics. These structural folds could be potentially useful for directing in vivo protein assemblies with predetermined spacing and stabilities.

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Fig. 1: The amyloid-like structure of αAmmem.
Fig. 2: Design of cross-α amyloid-like assembly.
Fig. 3: The aggregation behavior and fibril formation of the water-soluble peptides and the crystal structures of the cross-α amyloid-like fibrils.
Fig. 4: Packing of αAmL as a helical polymer composed of helix tetramers and its configurational relationship with the cross-α amyloid-like assembly of αAmG and αAmS.
Fig. 5: EGFP-tagged αAm peptides form inclusions in the cytosol of mammalian cells; αAmG, αAmA and αAmS form a solid-like phase, whereas αAmL is more mobile.

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Acknowledgements

We thank D. Bulkley, P. Jin, S. Li, X. Liu, N. Polizzi, N. Schmidt and H. Wu for technical help. This work was primarily supported by NIH grant R35GM122603 to W.F.D., with additional support from the NSF (CHE1413295) for the MRSEC program to the LRSM at the University of Pennsylvania. H.T.K. was supported by a Ruth L. Kirschstein NRSA Postdoctoral Fellowship (F32GM125217). Y.L. was supported by a Howard Hughes Medical Institute-Helen Hay Whitney Foundation Postdoctoral Fellowship.

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  1. These authors contributed equally: Hai Huang, Junjiao Yang.

Authors and Affiliations

  1. Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA

    Shao-Qing Zhang

  2. Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA

    Shao-Qing Zhang, Junjiao Yang, Huong T. Kratochvil, Xiaokun Shu & William F. DeGrado

  3. Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA, USA

    Shao-Qing Zhang, Hai Huang, Junjiao Yang, Huong T. Kratochvil, Marco Lolicato, Xiaokun Shu, Lijun Liu & William F. DeGrado

  4. Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA

    Yanxin Liu

  5. DLX Scientific, Lawrence, KS, USA

    Lijun Liu

  6. Institute for Neurodegenerative Diseases, University of California at San Francisco, San Francisco, CA, USA

    William F. DeGrado

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Contributions

S.-Q.Z. and W.F.D. conceived the project. S.-Q.Z. designed all the peptide sequences and performed in vitro experiments with H.T.K., M.L. and Y.L. H.H. and J.Y. conducted cellular in vivo experiments. L.L. solved and refined all the crystal structures. S.-Q.Z., H.H, J.Y., H.T.K., Y.L., X.S., L.L. and W.F.D. analyzed the data. S.-Q.Z. and W.F.D. prepared the manuscript with contributions from all the authors.

Corresponding authors

Correspondence to Xiaokun Shu, Lijun Liu or William F. DeGrado.

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Zhang, SQ., Huang, H., Yang, J. et al. Designed peptides that assemble into cross-α amyloid-like structures. Nat Chem Biol 14, 870–875 (2018). https://doi.org/10.1038/s41589-018-0105-5

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