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.

  • Review Article
  • Published:

The activities of amyloids from a structural perspective

Nature volume 539, pages 227–235 (2016)Cite this article

Subjects

Abstract

The aggregation of proteins into structures known as amyloids is observed in many neurodegenerative diseases, including Alzheimer's disease. Amyloids are composed of pairs of tightly interacting, many stranded and repetitive intermolecular β-sheets, which form the cross-β-sheet structure. This structure enables amyloids to grow by recruitment of the same protein and its repetition can transform a weak biological activity into a potent one through cooperativity and avidity. Amyloids therefore have the potential to self-replicate and can adapt to the environment, yielding cell-to-cell transmissibility, prion infectivity and toxicity.

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: Atomic-resolution X-ray diffraction steric-zipper structures of amyloid protofilaments formed by short segments of amyloid-forming proteins.
Figure 2: Solid-state NMR structure of the ordered portion of the amyloid fibril formed by the AD-related peptide amyloid-β(1–42).
Figure 3: 3D structure of the cores of the α-synuclein fibrils and the HET-s(218–289) prion.
Figure 4: Polymorphic atomic-resolution X-ray structures of amyloid fibrils formed by fragments of amyloid-β, viewed along the axes of the fibrils.
Figure 5: The replication of amyloids.
Figure 6: The adaptation of amyloids to various environments.

Similar content being viewed by others

References

  1. Sipe, J. D. et al. Nomenclature 2014: amyloid fibril proteins and clinical classification of the amyloidosis. Amyloid 21, 221–224 (2014).

    Article  PubMed  Google Scholar 

  2. Gustavsson, A., Engström, U. & Westermark, P. Normal transthyretin and synthetic transthyretin fragments form amyloid-like fibrils in vitro. Biochem. Biophys. Res. Commun. 175, 1159–1164 (1991).

    Article  CAS  PubMed  Google Scholar 

  3. Colon, W. & Kelly, J. W. Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro. Biochemistry 31, 8654–8660 (1992).

    Article  CAS  PubMed  Google Scholar 

  4. Booth, D. R. et al. Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis. Nature 385, 787–793 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  5. Fowler, D. M., Koulov, A. V., Balch, W. E. & Kelly, J. W. Functional amyloid — from bacteria to humans. Trends Biochem. Sci. 32, 217–224 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Chiti, F. & Dobson, C. M. Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem. 75, 333–366 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Knowles, T. P. J., Vendruscolo, M. & Dobson, C. M. The amyloid state and its association with protein misfolding diseases. Nature Rev. Mol. Cell Biol. 15, 384–396 (2014).

    Article  CAS  Google Scholar 

  9. Greenwald, J. & Riek, R. Biology of amyloid: structure, function, and regulation. Structure 18, 1244–1260 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Eisenberg, D. & Jucker, M. The amyloid state of proteins in human diseases. Cell 148, 1188–1203 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Eisele, Y. S. et al. Targeting protein aggregation for the treatment of degenerative diseases. Nature Rev. Drug Discov. 14, 759–780 (2015).

    Article  ADS  CAS  Google Scholar 

  12. Maury, C. P. J. The emerging concept of functional amyloid. J. Intern. Med. 265, 329–334 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Maji, S. K. et al. Functional amyloids as natural storage of peptide hormones in pituitary secretory granules. Science 325, 328–332 (2009).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sunde, M. et al. Common core structure of amyloid fibrils by synchrotron X-ray diffraction. J. Mol. Biol. 273, 729–739 (1997). Evidence that amyloid fibrils, in general, are composed of the cross-β-sheet structure.

    Article  CAS  PubMed  Google Scholar 

  15. Jiménez, J. L. et al. The protofilament structure of insulin amyloid fibrils. Proc. Natl Acad. Sci. USA 99, 9196–9201 (2002). The first atomic-resolution structures of amyloid-like crystals, which revealed the steric-zipper side-chain motif, including the Asn and Gln hydrogen-bond ladders.

    Article  ADS  PubMed  CAS  PubMed Central  Google Scholar 

  16. Nelson, R. et al. Structure of the cross-β spine of amyloid-like fibrils. Nature 435, 773–778 (2005).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sawaya, M. R. et al. Atomic structures of amyloid cross-β spines reveal varied steric zippers. Nature 447, 453–457 (2007). The various classes of cross-β-sheet structures are revealed at atomic resolution.

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Ivanova, M. I., Sievers, S. A., Sawaya, M. R., Wall, J. S. & Eisenberg, D. Molecular basis for insulin fibril assembly. Proc. Natl Acad. Sci. USA 106, 18990–18995 (2009).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wiltzius, J. J. W., Sievers, S. A., Sawaya, M. R. & Eisenberg, D. Atomic structures of IAPP (amylin) fusions suggest a mechanism for fibrillation and the role of insulin in the process. Protein Sci. 18, 1521–1530 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wiltzius, J. J. W. et al. Molecular mechanisms for protein-encoded inheritance. Nature Struct. Mol. Biol. 16, 973–978 (2009).

    Article  CAS  Google Scholar 

  21. Colletier, J.-P. et al. Molecular basis for amyloid-β polymorphism. Proc. Natl Acad. Sci. USA 108, 16938–16943 (2011).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  22. Apostol, M. I., Sawaya, M. R., Cascio, D. & Eisenberg, D. Crystallographic studies of prion protein (PrP) segments suggest how structural changes encoded by polymorphism at residue 129 modulate susceptibility to human prion disease. J. Biol. Chem. 285, 29671–29675 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Apostol, M. I., Wiltzius, J. J. W., Sawaya, M. R., Cascio, D. & Eisenberg, D. Atomic structures suggest determinants of transmission barriers in mammalian prion disease. Biochemistry 50, 2456–2463 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Soriaga, A. B., Sangwan, S., Macdonald, R., Sawaya, M. R. & Eisenberg, D. Crystal structures of IAPP amyloidogenic segments reveal a novel packing motif of out-of-register beta sheets. J. Phys. Chem. B 120, 5810–5816 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Saelices, L. et al. Uncovering the mechanism of aggregation of human transthyretin. J. Biol. Chem. 290, 28932–28943 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rodriguez, J. A. et al. Structure of the toxic core of α-synuclein from invisible crystals. Nature 525, 486–490 (2015).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  27. Balbirnie, M., Grothe, R. & Eisenberg, D. S. An amyloid-forming peptide from the yeast prion Sup35 reveals a dehydrated β-sheet structure for amyloid. Proc. Natl Acad. Sci. USA 98, 2375–2380 (2001).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tsemekhman, K., Goldschmidt, L., Eisenberg, D. & Baker, D. Cooperative hydrogen bonding in amyloid formation. Protein Sci. 16, 761–764 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Landreh, M. et al. The formation, function and regulation of amyloids: insights from structural biology. J. Intern. Med. 280, 164–176 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Liu, C. et al. Out-of-register β-sheets suggest a pathway to toxic amyloid aggregates. Proc. Natl Acad. Sci. USA 109, 20913–20918 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  31. van der Wel, P. C. A., Lewandowski, J. R. & Griffin, R. G. Solid-state NMR study of amyloid nanocrystals and fibrils formed by the peptide GNNQQNY from yeast prion protein Sup35p. J. Am. Chem. Soc. 129, 5117–5130 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Schmidt, M. et al. Peptide dimer structure in an Aβ(1–42) fibril visualized with cryo-EM. Proc. Natl Acad. Sci. USA 112, 11858–11863 (2015). The cryo-EM reconstruction of an amyloid-β(1–42) fibril reveals an intermolecular steric-zipper motif.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  33. Colvin, M. T. et al. Atomic resolution structure of monomorphic Aβ42 amyloid fibrils. J. Am. Chem. Soc. 138, 9663–9674 (2016). Refs 33 and 34 present the atomic-resolution solid-state NMR structure of an amyloid-β(1–42) fibril associated with AD, revealing hydrophobic interactions in concert with the cross-β-sheet motif as important contributors to the amyloid structure.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wälti, M. A. et al. Atomic-resolution structure of a disease-relevant Aβ(1–42) amyloid fibril. Proc. Natl Acad. Sci. USA 113, E4976–E4984 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Xiao, Y. et al. Aβ(1–42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease. Nature Struct. Mol. Biol. 22, 499–505 (2015).

    Article  CAS  Google Scholar 

  36. Tuttle, M. D. et al. Solid-state NMR structure of a pathogenic fibril of full-length human α-synuclein. Nature Struct. Mol. Biol. 23, 409–415 (2016). A solid-state NMR structure of cell-infectious amyloid fibrils of α-synuclein associated with PD.

    Article  CAS  Google Scholar 

  37. Terry, C. et al. Ex vivo mammalian prions are formed of paired double helical prion protein fibrils. Open Biol. 6, 160035 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Vázquez-Fernández, E. et al. The structural architecture of an infectious mammalian prion using electron cryomicroscopy. PLoS Pathog. 12, e1005835 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Groveman, B. R. et al. Parallel in-register intermolecular β-sheet architectures for prion-seeded prion protein (PrP) amyloids. J. Biol. Chem. 289, 24129–24142 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Helmus, J. J., Surewicz, K., Nadaud, P. S., Surewicz, W. K. & Jaroniec, C. P. Molecular conformation and dynamics of the Y145Stop variant of human prion protein in amyloid fibrils. Proc. Natl Acad. Sci. USA 105, 6284–6289 (2008).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  41. Müller, H. et al. Progress towards structural understanding of infectious sheep PrP-amyloid. Prion 8, 344–358 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Jones, E. M. et al. Structural polymorphism in amyloids: new insights from studies with Y145Stop prion protein fibrils. J. Biol. Chem. 286, 42777–42784 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Coustou, V., Deleu, C., Saupe, S. & Begueret, J. The protein product of the het-s heterokaryon incompatibility gene of the fungus Podospora anserina behaves as a prion analog. Proc. Natl Acad. Sci. USA 94, 9773–9778 (1997).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wasmer, C. et al. Amyloid fibrils of the HET-s(218–289) prion form a β solenoid with a triangular hydrophobic core. Science 319, 1523–1526 (2008). The 3D structure of a biological-relevant functional amyloid reveals a β-solenoid helix with two windings per molecules, indicating an evolutionarily-evolved prion.

    Article  ADS  CAS  PubMed  Google Scholar 

  45. Klabunde, T. et al. Rational design of potent human transthyretin amyloid disease inhibitors. Nature Struct. Biol. 7, 312–321 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Vilar, M. et al. The fold of α-synuclein fibrils. Proc. Natl Acad. Sci. USA 105, 8637–8642 (2008).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bousset, L. et al. Structural and functional characterization of two alpha-synuclein strains. Nature Commun. 4, 2575 (2013). Two α-synuclein polymorphs with distinct structures at both the atomic and the mesoscopic levels show distinct toxicities.

    Article  ADS  CAS  Google Scholar 

  48. Meinhardt, J., Sachse, C., Hortschansky, P., Grigorieff, N. & Fändrich, M. Aβ(1–40) fibril polymorphism implies diverse interaction patterns in amyloid fibrils. J. Mol. Biol. 386, 869–877 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Ravotti, F. et al. Solid-state NMR sequential assignment of an amyloid-β(1–42) fibril polymorph. Biomol. NMR Assign. 10, 269–276 (2016).

    Article  CAS  Google Scholar 

  50. Tycko, R. Physical and structural basis for polymorphism in amyloid fibrils. Protein Sci. 23, 1528–1539 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Paravastu, A. K., Leapman, R. D., Yau, W.-M. & Tycko, R. Molecular structural basis for polymorphism in Alzheimer's β-amyloid fibrils. Proc. Natl Acad. Sci. USA 105, 18349–18354 (2008).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  52. Petkova, A. T. et al. Self-propagating, molecular-level polymorphism in Alzheimer's β-amyloid fibrils. Science 307, 262–265 (2005). The presence of self-propagating polymorphs is revealed at the atomic level using solid-state NMR.

    Article  ADS  CAS  PubMed  Google Scholar 

  53. Anfinsen, C. B. Principles that govern the folding of protein chains. Science 181, 223–230 (1973).

    Article  ADS  CAS  PubMed  Google Scholar 

  54. Daskalov, A. et al. Contribution of specific residues of the β-solenoid fold to HET-s prion function, amyloid structure and stability. PLoS Pathog. 10, e1004158 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Wang, L., Schubert, D., Sawaya, M. R., Eisenberg, D. & Riek, R. Multidimensional structure-activity relationship of a protein in its aggregated states. Angew. Chem. Int. Edn Engl. 49, 3904–3908 (2010).

    Article  CAS  Google Scholar 

  56. Silva, J. L., De Moura Gallo, C. V., Costa, D. C. F. & Rangel, L. P. Prion-like aggregation of mutant p53 in cancer. Trends Biochem. Sci. 39, 260–267 (2014).

    Article  CAS  PubMed  Google Scholar 

  57. Ano Bom, A. P. D. et al. Mutant p53 aggregates into prion-like amyloid oligomers and fibrils: implications for cancer. J. Biol. Chem. 287, 28152–28162 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Soragni, A. et al. A designed inhibitor of p53 aggregation rescues p53 tumor suppression in ovarian carcinomas. Cancer Cell 29, 90–103 (2016).

    Article  CAS  PubMed  Google Scholar 

  59. Xu, J. et al. Gain of function of mutant p53 by coaggregation with multiple tumor suppressors. Nature Chem. Biol. 7, 285–295 (2011).

    Article  CAS  Google Scholar 

  60. Riek, R. & Saupe, S. J. The HET-S/s prion motif in the control of programmed cell death. Cold Spring Harb. Perspect. Biol. 8, a023515 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Seuring, C. et al. The mechanism of toxicity in HET-S/HET-s prion incompatibility. PLoS Biol. 10, e1001451 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Caudron, F. & Barral, Y. A super-assembly of Whi3 encodes memory of deceptive encounters by single cells during yeast courtship. Cell 155, 1244–1257 (2013).

    Article  CAS  PubMed  Google Scholar 

  63. Si, K., Choi, Y.-B., White-Grindley, E., Majumdar, A. & Kandel, E. R. Aplysia CPEB can form prion-like multimers in sensory neurons that contribute to long-term facilitation. Cell 140, 421–435 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Si, K., Lindquist, S. & Kandel, E. R. A neuronal isoform of the aplysia CPEB has prion-like properties. Cell 115, 879–891 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Geoghegan, J. C. et al. Selective incorporation of polyanionic molecules into hamster prions. J. Biol. Chem. 282, 36341–36353 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Supattapone, S. Elucidating the role of cofactors in mammalian prion propagation. Prion 8, 100–105 (2014).

    Article  CAS  PubMed  Google Scholar 

  67. Prusiner, S. B. Prions. Proc. Natl Acad. Sci. USA 95, 13363–13383 (1998).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  68. Tanaka, M., Chien, P., Naber, N., Cooke, R. & Weissman, J. S. Conformational variations in an infectious protein determine prion strain differences. Nature 428, 323–328 (2004).

    Article  ADS  CAS  PubMed  Google Scholar 

  69. Cohen, S. I. A. et al. Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism. Proc. Natl Acad. Sci. USA 110, 9758–9763 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  70. Arosio, P., Knowles, T. P. J. & Linse, S. On the lag phase in amyloid fibril formation. Phys. Chem. Chem. Phys. 17, 7606–7618 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Riek, R. Cell biology: infectious Alzheimer's disease? Nature 444, 429–431 (2006).

    Article  ADS  CAS  PubMed  Google Scholar 

  72. Meyer-Luehmann, M. et al. Exogenous induction of cerebral β-amyloidogenesis is governed by agent and host. Science 313, 1781–1784 (2006). Demonstrates that aggregates of amyloid-β(1–42) are transmissible in a mouse model of AD.

    Article  ADS  CAS  PubMed  Google Scholar 

  73. Chernoff, Y. O., Lindquist, S. L., Ono, B., Inge-Vechtomov, S. G. & Liebman, S. W. Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+]. Science 268, 880–884 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  74. Alper, T., Cramp, W. A., Haig, D. A. & Clarke, M. C. Does the agent of scrapie replicate without nucleic acid? Nature 214, 764–766 (1967).

    Article  ADS  CAS  PubMed  Google Scholar 

  75. Griffith, J. S. Self-replication and scrapie. Nature 215, 1043–1044 (1967).

    Article  ADS  CAS  PubMed  Google Scholar 

  76. Prusiner, S. B. Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144 (1982).

    Article  ADS  CAS  PubMed  Google Scholar 

  77. Serio, T. R. & Lindquist, S. L. [PSI+], SUP35, and chaperones. Adv. Protein Chem. 57, 335–366 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Wickner, R. B. et al. Yeast prions act as genes composed of self-propagating protein amyloids. Adv. Protein Chem. 57, 313–334 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Edskes, H. K., Gray, V. T. & Wickner, R. B. The [URE3] prion is an aggregated form of Ure2p that can be cured by overexpression of Ure2p fragments. Proc. Natl Acad. Sci. USA 96, 1498–1503 (1999).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  80. Patino, M. M., Liu, J. J., Glover, J. R. & Lindquist, S. Support for the prion hypothesis for inheritance of a phenotypic trait in yeast. Science 273, 622–626 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  81. Castilla, J., Saá, P., Hetz, C. & Soto, C. In vitro generation of infectious scrapie prions. Cell 121, 195–206 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Wang, F., Wang, X., Yuan, C.-G. & Ma, J. Generating a prion with bacterially expressed recombinant prion protein. Science 327, 1132–1135 (2010).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ritter, C. et al. Correlation of structural elements and infectivity of the HET-s prion. Nature 435, 844–848 (2005).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  84. Jucker, M. & Walker, L. C. Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann. Neurol. 70, 532–540 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Walsh, D. M. & Selkoe, D. J. A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration. Nature Rev. Neurosci. 17, 251–260 (2016).

    Article  CAS  Google Scholar 

  86. Morales, R., Bravo-Alegria, J., Duran-Aniotz, C. & Soto, C. Titration of biologically active amyloid-β seeds in a transgenic mouse model of Alzheimer's disease. Sci. Rep. 5, 9349 (2015).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  87. Wu, J. W. et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nature Neurosci. 19, 1085–1092 (2016).

    Article  CAS  PubMed  Google Scholar 

  88. Luk, K. C. et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949–953 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  89. Lundmark, K. et al. Transmissibility of systemic amyloidosis by a prion-like mechanism. Proc. Natl Acad. Sci. USA 99, 6979–6984 (2002).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  90. Jaunmuktane, Z. et al. Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature 525, 247–250 (2015). Demonstrates that amyloid-β(1–42) pathology is transmissible in humans.

    Article  ADS  CAS  PubMed  Google Scholar 

  91. Ridley, R. M., Baker, H. F., Windle, C. P. & Cummings, R. M. Very long term studies of the seeding of β-amyloidosis in primates. J. Neural Transm. 113, 1243–1251 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Lu, J.-X. et al. Molecular structure of β-amyloid fibrils in Alzheimer's disease brain tissue. Cell 154, 1257–1268 (2013).

    Article  CAS  PubMed  Google Scholar 

  93. Aguzzi, A. & Lakkaraju, A. K. K. Cell biology of prions and prionoids: a status report. Trends Cell Biol. 26, 40–51 (2016).

    Article  CAS  PubMed  Google Scholar 

  94. Aguzzi, A. & Rajendran, L. The transcellular spread of cytosolic amyloids, prions, and prionoids. Neuron 64, 783–790 (2009).

    Article  CAS  PubMed  Google Scholar 

  95. Weissmann, C. Birth of a prion: spontaneous generation revisited. Cell 122, 165–168 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Asante, E. A. et al. BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein. EMBO J. 21, 6358–6366 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Cali, I. et al. Co-existence of scrapie prion protein types 1 and 2 in sporadic Creutzfeldt-Jakob disease: its effect on the phenotype and prion-type characteristics. Brain 132, 2643–2658 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Sigurdson, C. J. et al. Prion strain discrimination using luminescent conjugated polymers. Nature Methods 4, 1023–1030 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Cali, I. et al. Classification of sporadic Creutzfeldt-Jakob disease revisited. Brain 129, 2266–2277 (2006).

    Article  PubMed  Google Scholar 

  100. King, C.-Y. & Diaz-Avalos, R. Protein-only transmission of three yeast prion strains. Nature 428, 319–323 (2004).

    Article  ADS  CAS  PubMed  Google Scholar 

  101. Toyama, B. H., Kelly, M. J. S., Gross, J. D. & Weissman, J. S. The structural basis of yeast prion strain variants. Nature 449, 233–237 (2007).

    Article  ADS  CAS  PubMed  Google Scholar 

  102. Li, J., Browning, S., Mahal, S. P., Oelschlegel, A. M. & Weissmann, C. Darwinian evolution of prions in cell culture. Science 327, 869–872 (2010). Evidence for the adaptation of prions.

    Article  ADS  CAS  PubMed  Google Scholar 

  103. Weissmann, C., Li, J., Mahal, S. P. & Browning, S. Prions on the move. EMBO Rep. 12, 1109–1117 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Oelschlegel, A. M. & Weissmann, C. Acquisition of drug resistance and dependence by prions. PLoS Pathog. 9, e1003158 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Collinge, J. & Clarke, A. R. A general model of prion strains and their pathogenicity. Science 318, 930–936 (2007).

    Article  ADS  CAS  PubMed  Google Scholar 

  106. Eigen, M. Selforganization of matter and the evolution of biological macromolecules. Naturwissenschaften 58, 465–523 (1971).

    Article  ADS  CAS  PubMed  Google Scholar 

  107. Spillantini, M. G. et al. α-Synuclein in Lewy bodies. Nature 388, 839–840 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  108. Goldgaber, D., Lerman, M. I., McBride, O. W., Saffiotti, U. & Gajdusek, D. C. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. Science 235, 877–880 (1987).

    Article  ADS  CAS  PubMed  Google Scholar 

  109. Tanzi, R. E. et al. Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 235, 880–884 (1987).

    Article  ADS  CAS  PubMed  Google Scholar 

  110. Suzuki, N. et al. An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science 264, 1336–1340 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  111. Birk, J., Friberg, M. A., Prescianotto-Baschong, C., Spiess, M. & Rutishauser, J. Dominant pro-vasopressin mutants that cause diabetes insipidus form disulfide-linked fibrillar aggregates in the endoplasmic reticulum. J. Cell Sci. 122, 3994–4002 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. Chesebro, B. et al. Anchorless prion protein results in infectious amyloid disease without clinical scrapie. Science 308, 1435–1439 (2005).

    Article  ADS  CAS  PubMed  Google Scholar 

  113. Sandberg, M. K., Al-Doujaily, H., Sharps, B., Clarke, A. R. & Collinge, J. Prion propagation and toxicity in vivo occur in two distinct mechanistic phases. Nature 470, 540–542 (2011).

    Article  ADS  CAS  PubMed  Google Scholar 

  114. Walsh, D. M. & Selkoe, D. J. Aβ oligomers — a decade of discovery. J. Neurochem. 101, 1172–1184 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. Hardy, J. A. & Higgins, G. A. Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992).

    Article  ADS  CAS  PubMed  Google Scholar 

  116. Silveira, J. R. et al. The most infectious prion protein particles. Nature 437, 257–261 (2005).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  117. Pieri, L., Madiona, K., Bousset, L. & Melki, R. Fibrillar α-synuclein and huntingtin exon 1 assemblies are toxic to the cells. Biophys. J. 102, 2894–2905 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  118. Jarrett, J. T. & Lansbury, P. T. Seeding 'one-dimensional crystallization' of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie? Cell 73, 1055–1058 (1993).

    Article  CAS  PubMed  Google Scholar 

  119. Lashuel, H. A., Hartley, D., Petre, B. M., Walz, T. & Lansbury, P. T. Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418, 291 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

  120. Abedini, A. et al. Time-resolved studies define the nature of toxic IAPP intermediates, providing insight for anti-amyloidosis therapeutics. eLife 5, e12977 (2016).

    Article  MathSciNet  PubMed  PubMed Central  CAS  Google Scholar 

  121. Cohen, S. I. A. et al. A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers. Nature Struct. Mol. Biol. 22, 207–213 (2015).

    Article  CAS  Google Scholar 

  122. Laganowsky, A. et al. Atomic view of a toxic amyloid small oligomer. Science 335, 1228–1231 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  123. Jan, A. et al. Aβ42 neurotoxicity is mediated by ongoing nucleated polymerization process rather than by discrete Aβ42 species. J. Biol. Chem. 286, 8585–8596 (2011).

    Article  CAS  PubMed  Google Scholar 

  124. Reynolds, N. P. et al. Mechanism of membrane interaction and disruption by α-synuclein. J. Am. Chem. Soc. 133, 19366–19375 (2011).

    Article  CAS  PubMed  Google Scholar 

  125. Ankarcrona, M. et al. Current and future treatment of amyloid diseases. J. Intern. Med. 280, 177–202 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Knight, S. D., Presto, J., Linse, S. & Johansson, J. The BRICHOS domain, amyloid fibril formation, and their relationship. Biochemistry 52, 7523–7531 (2013).

    Article  CAS  PubMed  Google Scholar 

  127. Johnson, S. M., Connelly, S., Fearns, C., Powers, E. T. & Kelly, J. W. The transthyretin amyloidoses: from delineating the molecular mechanism of aggregation linked to pathology to a regulatory-agency-approved drug. J. Mol. Biol. 421, 185–203 (2012). A review on the successful development of a drug through stabilizing the native form of the amyloid protein.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Eisenberg, D. S. & Sawaya, M. R. Implications for Alzheimer's disease of an atomic resolution structure of amyloid-β(1–42) fibrils. Proc. Natl Acad. Sci. USA 113, 9398–9400 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Sunde, M. & Blake, C. The structure of amyloid fibrils by electron microscopy and X-ray diffraction. Adv. Protein Chem. 50, 123–159 (1997).

    Article  CAS  PubMed  Google Scholar 

  130. Astbury, W. T., Dickinson, S. & Bailey, K. The X-ray interpretation of denaturation and the structure of the seed globulins. Biochem. J. 29, 2351–2360 (1935). The cross-β-sheet structure is introduced on the basis of X-ray fibre diffraction studies of protein aggregates induced by heat denaturation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Asakura, S. Polymerization of flagellin and polymorphism of flagella. Adv. Biophys. 1, 99–155 (1970).

    CAS  PubMed  Google Scholar 

  132. Oosawa, F. & Asakura, S. Thermodynamics of the Polymerization of Protein (Academic, 1975).

    Google Scholar 

  133. Bishop, M. F. & Ferrone, F. A. Kinetics of nucleation-controlled polymerization. A perturbation treatment for use with a secondary pathway. Biophys. J. 46, 631–644 (1984).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  134. Pronchik, J., He, X., Giurleo, J. T. & Talaga, D. S. In vitro formation of amyloid from α-synuclein is dominated by reactions at hydrophobic interfaces. J. Am. Chem. Soc. 132, 9797–9803 (2010).

    Article  CAS  PubMed  Google Scholar 

  135. Campioni, S. et al. The presence of an air-water interface affects formation and elongation of α-synuclein fibrils. J. Am. Chem. Soc. 136, 2866–2875 (2014).

    Article  CAS  PubMed  Google Scholar 

  136. Knowles, T. P. J. et al. An analytical solution to the kinetics of breakable filament assembly. Science 326, 1533–1537 (2009).

    Article  ADS  CAS  PubMed  Google Scholar 

  137. Hurshman, A. R., White, J. T., Powers, E. T. & Kelly, J. W. Transthyretin aggregation under partially denaturing conditions is a downhill polymerization. Biochemistry 43, 7365–7381 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank K. Comiotto and M. Sawaya for making figures and the Swiss National Science Foundation (SNSF), the US National Institutes of Health and the Howard Hughes Medical Institute for continuing support of our research, including an SNSF Sinergia grant to R.R.

Author information

Authors and Affiliations

  1. Department of Chemistry and Applied Biosciences, Laboratory of Physical Chemistry, ETH Zurich, Zürich, 8093, Switzerland

    Roland Riek

  2. UCLA-DOE Institute, Los Angeles, 90095-1570, California, USA

    David S. Eisenberg

  3. Howard Hughes Medical Institute, Los Angeles, 90095-1570, California, USA

    David S. Eisenberg

Authors
  1. Roland Riek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David S. Eisenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Roland Riek or David S. Eisenberg.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Reprints and permissions information is available at www.nature.com/reprints.

Reviewer Information Nature thanks G. Pielak and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Riek, R., Eisenberg, D. The activities of amyloids from a structural perspective. Nature 539, 227–235 (2016). https://doi.org/10.1038/nature20416

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature20416

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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