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Molecular mechanisms for protein-encoded inheritance

Nature Structural & Molecular Biology volume 16, pages 973–978 (2009)Cite this article

Abstract

In prion inheritance and transmission, strains are phenotypic variants encoded by protein 'conformations'. However, it is unclear how a protein conformation can be stable enough to endure transmission between cells or organisms. Here we describe new polymorphic crystal structures of segments of prion and other amyloid proteins, which offer two structural mechanisms for the encoding of prion strains. In packing polymorphism, prion strains are encoded by alternative packing arrangements (polymorphs) of β-sheets formed by the same segment of a protein; in segmental polymorphism, prion strains are encoded by distinct β-sheets built from different segments of a protein. Both forms of polymorphism can produce enduring conformations capable of encoding strains. These molecular mechanisms for transfer of protein-encoded information into prion strains share features with the familiar mechanism for transfer of nucleic acid–encoded information into microbial strains, including sequence specificity and recognition by noncovalent bonds.

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Figure 1: Packing polymorphism of steric zippers, determined by X-ray microcrystallography.
Figure 2: Segmental polymorphism in IAPP.
Figure 3: Evidence for at least two steric zipper polymorphs in full-length IAPP.
Figure 4: Schematic summary of steric zipper mechanisms for amyloid and prion polymorphism.

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Protein Data Bank

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Acknowledgements

We thank the NE-CAT beamline at the Advanced Photon Source and ID-13 beamline at the European Synchrotron Radiation Facility for beam time and collection assistance, and the National Science Foundation, National Institutes of Health and Howard Hughes Medical Institute for financial support, and P. Chien for discussion.

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Author notes

  1. Jed J W Wiltzius, Meytal Landau, Rebecca Nelson, Michael R Sawaya and Marcin I Apostol: These authors contributed equally to this work.

Authors and Affiliations

  1. UCLA-DOE Institute for Genomics and Proteomics, Howard Hughes Medical Institute, Molecular Biology Institute, University of California, Los Angeles, California, USA

    Jed J W Wiltzius, Meytal Landau, Rebecca Nelson, Michael R Sawaya, Marcin I Apostol, Lukasz Goldschmidt, Angela B Soriaga, Duilio Cascio & David Eisenberg

  2. NE-CAT and Department of Chemistry and Chemical Biology, Cornell University, Argonne National Laboratory, Argonne, Illinois, USA

    Kanagalaghatta Rajashankar

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Contributions

J.J.W.W., M.L., R.N., M.I.A. and M.R.S. planned, executed and analyzed the research and coauthored the paper; L.G. planned and analyzed the research; A.B.S. executed and analyzed the research; D.C. and K.R. collected the X-ray diffraction data; and D.E. supervised the research and coauthored the paper.

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Correspondence to David Eisenberg.

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Supplementary Figures 1–5 and Supplementary Table 1 and Supplementary Methods (PDF 760 kb)

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Wiltzius, J., Landau, M., Nelson, R. et al. Molecular mechanisms for protein-encoded inheritance. Nat Struct Mol Biol 16, 973–978 (2009). https://doi.org/10.1038/nsmb.1643

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