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Generic nature of the condensed states of proteins

Nature Cell Biology volume 23, pages 587–594 (2021)Cite this article

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Abstract

Proteins undergoing liquid–liquid phase separation are being discovered at an increasing rate. Since at the high concentrations present in the cell most proteins would be expected to form a liquid condensed state, this state should be considered to be a fundamental state of proteins along with the native state and the amyloid state. Here we discuss the generic nature of the liquid-like and solid-like condensed states, and describe a wide variety of biological functions conferred by these condensed states.

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Fig. 1: Fundamental nature of the native, droplet and amyloid states of proteins.
Fig. 2: Cellular functions of proteins in the native and condensed states.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Vecchi, G. et al. Proteome-wide observation of the phenomenon of life on the edge of solubility. Proc. Natl Acad. Sci. USA 117, 1015–1020 (2020).

    Article  CAS  PubMed  Google Scholar 

  3. Hardenberg, M., Horvath, A., Ambrus, V., Fuxreiter, M. & Vendruscolo, M. Widespread occurrence of the droplet state of proteins in the human proteome. Proc. Natl Acad. Sci. USA 117, 33254–33262 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Banani, S. F., Lee, H. O., Hyman, A. A. & Rosen, M. K. Biomolecular condensates: organizers of cellular biochemistry. Nat. Rev. Mol. Cell Biol. 18, 285–298 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Brangwynne, C. P., Tompa, P. & Pappu, R. V. Polymer physics of intracellular phase transitions. Nat. Phys. 11, 899–904 (2015).

    Article  CAS  Google Scholar 

  6. Alberti, S. The wisdom of crowds: regulating cell function through condensed states of living matter. J. Cell Sci. 130, 2789–2796 (2017).

    CAS  PubMed  Google Scholar 

  7. Tartaglia, G. G., Pechmann, S., Dobson, C. M. & Vendruscolo, M. Life on the edge: a link between gene expression levels and aggregation rates of human proteins. Trends Biochem. Sci. 32, 204–206 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Sormanni, P. et al. Simultaneous quantification of protein order and disorder. Nat. Chem. Biol. 13, 339–342 (2017).

    Article  CAS  PubMed  Google Scholar 

  9. Lin, Y., Protter, D. S., Rosen, M. K. & Parker, R. Formation and maturation of phase-separated liquid droplets by RNA-binding proteins. Mol. Cell 60, 208–219 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Li, P. et al. Phase transitions in the assembly of multivalent signalling proteins. Nature 483, 336–340 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sawaya, M. R. et al. Atomic structures of amyloid cross-beta spines reveal varied steric zippers. Nature 447, 453–457 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Reichheld, S. E., Muiznieks, L. D., Keeley, F. W. & Sharpe, S. Direct observation of structure and dynamics during phase separation of an elastomeric protein. Proc. Natl Acad. Sci. USA 114, E4408–E4415 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Blake, C. C., Mair, G. A., North, A. C., Phillips, D. C. & Sarma, V. R. On the conformation of the hen egg-white lysozyme molecule. Proc. R. Soc. Lond. B 167, 365–377 (1967).

    Article  CAS  PubMed  Google Scholar 

  14. Wilson, K. P. et al. Structure and mechanism of interleukin-1β converting enzyme. Nature 370, 270–275 (1994).

    Article  CAS  PubMed  Google Scholar 

  15. Fuxreiter, M. & Warshel, A. Origin of the catalytic power of acetylcholineesterase. Computer simulation studies. J. Am. Chem. Soc. 120, 183–194 (1998).

    Article  CAS  Google Scholar 

  16. Aggarwal, A. K., Rodgers, D. W., Drottar, M., Ptashne, M. & Harrison, S. C. Recognition of a DNA operator by the repressor of phage 434: a view at high resolution. Science 242, 899–907 (1988).

    Article  CAS  PubMed  Google Scholar 

  17. Slupphaug, G. et al. A nucleotide-flipping mechanism from the structure of human uracil-DNA glycosylase bound to DNA. Nature 384, 87–92 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Hosfield, D. J., Guan, Y., Haas, B. J., Cunningham, R. P. & Tainer, J. A. Structure of the DNA repair enzyme endonuclease IV and its DNA complex: double-nucleotide flipping at abasic sites and three-metal-ion catalysis. Cell 98, 397–408 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Zhou, Y., Morais-Cabral, J. H., Kaufman, A. & MacKinnon, R. Chemistry of ion coordination and hydration revealed by a K+ channel–Fab complex at 2.0 Å resolution. Nature 414, 43–48 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Ciechanover, A. & Schwartz, A. L. How are substrates recognized by the ubiquitin-mediated proteolytic system? Trends Biochem. Sci. 14, 483–488 (1989).

    Article  CAS  PubMed  Google Scholar 

  21. Song, L. et al. Structure of staphylococcal α-hemolysin, a heptameric transmembrane pore. Science 274, 1859–1866 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Takizawa, M. et al. Mechanistic basis for the recognition of laminin-511 by α6β1 integrin. Sci. Adv. 3, e1701497 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Steitz, T. A. Visualizing polynucleotide polymerase machines at work. EMBO J. 25, 3458–3468 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ramakrishnan, V. Ribosome structure and the mechanism of translation. Cell 108, 557–572 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Manglik, A. et al. Structural Insights into the dynamic process of β2-adrenergic receptor signaling. Cell 161, 1101–1111 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cheng, X., Kumar, S., Posfai, J., Pflugrath, J. W. & Roberts, R. J. Crystal structure of the HhaI DNA methyltransferase complexed with S-adenosyl-l-methionine. Cell 74, 299–307 (1993).

    Article  CAS  PubMed  Google Scholar 

  27. Jiang, Y., Rossi, P. & Kalodimos, C. G. Structural basis for client recognition and activity of Hsp40 chaperones. Science 365, 1313–1319 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tompa, P. & Fuxreiter, M. Fuzzy complexes: polymorphism and structural disorder in protein-protein interactions. Trends Biochem. Sci. 33, 2–8 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Selenko, P. et al. Structural basis for the molecular recognition between human splicing factors U2AF65 and SF1/mBBP. Mol. Cell 11, 965–976 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Chaudhry, C. et al. Role of the gamma-phosphate of ATP in triggering protein folding by GroEL-GroES: function, structure and energetics. EMBO J. 22, 4877–4887 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Saleh, T., Rossi, P. & Kalodimos, C. G. Atomic view of the energy landscape in the allosteric regulation of Abl kinase. Nat. Struct. Mol. Biol. 24, 893–901 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. West, A., Brummel, B. E., Braun, A. R., Rhoades, E. & Sachs, J. N. Membrane remodeling and mechanics: Experiments and simulations of α-synuclein. Biochim. Biophys. Acta 1858, 1594–1609 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yuen, F. et al. Preferential adsorption to air-water interfaces: a novel cryoprotective mechanism for LEA proteins. Biochem. J. 476, 1121–1135 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Delaforge, E. et al. Deciphering the dynamic interaction profile of an intrinsically disordered protein by NMR exchange spectroscopy. J. Am. Chem. Soc. 140, 1148–1158 (2018).

    Article  CAS  PubMed  Google Scholar 

  35. Rowell, J. P., Simpson, K. L., Stott, K., Watson, M. & Thomas, J. O. HMGB1-facilitated p53 DNA binding occurs via HMG–Box/p53 transactivation domain interaction, regulated by the acidic tail. Structure 20, 2014–2024 (2012).

    Article  CAS  PubMed  Google Scholar 

  36. Lyon, A. S., Peeples, W. B. & Rosen, M. K. A framework for understanding the functions of biomolecular condensates across scales. Nat. Rev. Mol. Cell Biol. 22, 215–235 (2020).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Freeman Rosenzweig, E. S. et al. The eukaryotic CO2-concentrating organelle is liquid-like and exhibits dynamic reorganization. Cell 171, 148–162 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Fowler, D. M. et al. Functional amyloid formation within mammalian tissue. PLoS Biol. 4, e6 (2006).

    Article  PubMed  CAS  Google Scholar 

  39. Su, X. et al. Phase separation of signaling molecules promotes T cell receptor signal transduction. Science 352, 595–599 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schwarz-Romond, T., Metcalfe, C. & Bienz, M. Dynamic recruitment of axin by Dishevelled protein assemblies. J. Cell Sci. 120, 2402–2412 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Woodruff, J. B. et al. The centrosome is a selective condensate that nucleates microtubules by concentrating tubulin. Cell 169, 1066–1077.e10 (2017).

    Article  CAS  PubMed  Google Scholar 

  42. Banjade, S. & Rosen, M. K. Phase transitions of multivalent proteins can promote clustering of membrane receptors. 3, e04123 (2014).

  43. Case, L. B., Zhang, X., Ditlev, J. A. & Rosen, M. K. Stoichiometry controls activity of phase-separated clusters of actin signaling proteins. Science 363, 1093–1097 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Du, M. & Chen, Z. J. DNA-induced liquid phase condensation of cGAS activates innate immune signaling. Science 361, 704–709 (2018).

    Article  CAS  PubMed  Google Scholar 

  45. Li, J. et al. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 150, 339–350 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kilic, S. et al. Phase separation of 53BP1 determines liquid-like behavior of DNA repair compartments. EMBO J. 38, e101379 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Boija, A. et al. Transcription factors activate genes through the phase-separation capacity of their activation domains. Cell 175, 1842–1855.e16 (2018).

    Article  CAS  PubMed  Google Scholar 

  48. Larson, A. G. et al. Liquid droplet formation by HP1alpha suggests a role for phase separation in heterochromatin. Nature 547, 236–240 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zaffagnini, G. et al. p62 filaments capture and present ubiquitinated cargos for autophagy. EMBO J. 37, e98308 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Fujioka, Y. et al. Phase separation organizes the site of autophagosome formation. Nature 578, 301–305 (2020).

    Article  CAS  PubMed  Google Scholar 

  51. Claessen, D. et al. A novel class of secreted hydrophobic proteins is involved in aerial hyphae formation in Streptomyces coelicolor by forming amyloid-like fibrils. Genes Dev. 17, 1714–1726 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kwan, A. H. et al. Structural basis for rodlet assembly in fungal hydrophobins. Proc. Natl Acad. Sci. USA 103, 3621–3626 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Quiroz, F. G. et al. Liquid–liquid phase separation drives skin barrier formation. Science 367, eaax9554 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Iconomidou, V. A., Vriend, G. & Hamodrakas, S. J. Amyloids protect the silkmoth oocyte and embryo. FEBS Lett. 479, 141–145 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Boke, E. et al. Amyloid-like self-assembly of a cellular compartment. Cell 166, 637–650 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chapman, M. R. et al. Role of Escherichia coli curli operons in directing amyloid fiber formation. Science 295, 851–855 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Dueholm, M. S. et al. Functional amyloid in Pseudomonas. Mol. Microbiol. 77, 1009–1020 (2010).

    CAS  PubMed  Google Scholar 

  59. Miskei, M. et al. Fuzziness enables context dependence of protein interactions. FEBS Lett. 591, 2682–2695 (2017).

    Article  CAS  PubMed  Google Scholar 

  60. Wippich, F. et al. Dual specificity kinase DYRK3 couples stress granule condensation/dissolution to mTORC1 signaling. Cell 152, 791–805 (2013).

    Article  CAS  PubMed  Google Scholar 

  61. Milles, S. et al. Plasticity of an ultrafast interaction between nucleoporins and nuclear transport receptors. Cell 163, 734–745 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Frottin, F. et al. The nucleolus functions as a phase-separated protein quality control compartment. Science 365, 342–347 (2019).

    Article  CAS  PubMed  Google Scholar 

  63. Feric, M. et al. Coexisting liquid phases underlie nucleolar subcompartments. Cell 165, 1686–1697 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Krishnan, R. & Lindquist, S. L. Structural insights into a yeast prion illuminate nucleation and strain diversity. Nature 435, 765–772 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Baxa, U., Ross, P. D., Wickner, R. B. & Steven, A. C. The N-terminal prion domain of Ure2p converts from an unfolded to a thermally resistant conformation upon filament formation. J. Mol. Biol. 339, 259–264 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Ghosh, S. et al. p53 amyloid formation leading to its loss of function: implications in cancer pathogenesis. Cell Death Differ. 24, 1784–1798 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lin, S. C., Lo, Y. C. & Wu, H. Helical assembly in the MyD88–IRAK4–IRAK2 complex in TLR/IL-1R signalling. Nature 465, 885–890 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cai, X. et al. Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell 156, 1207–1222 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Chakrabortee, S. et al. Intrinsically disordered proteins drive emergence and inheritance of biological traits. Cell 167, 369–381.e12 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Shi, Y. et al. An autoinhibitory mechanism modulates MAVS activity in antiviral innate immune response. Nat. Commun. 6, 7811 (2015).

    Article  CAS  PubMed  Google Scholar 

  71. Hou, F. et al. MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell 146, 448–461 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Itakura, A. K., Chakravarty, A. K., Jakobson, C. M. & Jarosz, D. F. Widespread prion-based control of growth and differentiation strategies in saccharomyces cerevisiae. Mol. Cell 77, 266–278 (2020).

    Article  CAS  PubMed  Google Scholar 

  73. Zhao, Y., Chen, S., Swensen, A. C., Qian, W. J. & Gouaux, E. Architecture and subunit arrangement of native AMPA receptors elucidated by cryo-EM. Science 364, 355–362 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Milovanovic, D., Wu, Y., Bian, X. & De Camilli, P. A liquid phase of synapsin and lipid vesicles. Science 361, 604–607 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zeng, M. et al. Reconstituted postsynaptic density as a molecular platform for understanding synapse formation and plasticity. Cell 174, 1172–1187.e16 (2018).

    Article  CAS  PubMed  Google Scholar 

  76. Heinrich, S. U. & Lindquist, S. Protein-only mechanism induces self-perpetuating changes in the activity of neuronal Aplysia cytoplasmic polyadenylation element binding protein (CPEB). Proc. Natl Acad. Sci. USA 108, 2999–3004 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kirschner, M. & Gerhart, J. Evolvability. Proc. Natl Acad. Sci. USA 95, 8420–8427 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Gianni, S. et al. Fuzziness and frustration in the energy landscape of protein folding, function, and assembly. Acc. Chem. Res. 54, 1251–1259 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Miskei, M., Horvath, A., Vendruscolo, M. & Fuxreiter, M. Sequence-based prediction of fuzzy protein interactions. J. Mol. Biol. 432, 2289–2303 (2020).

    Article  CAS  PubMed  Google Scholar 

  80. Nott, T. J. et al. Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. Mol. Cell 57, 936–947 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Burke, K. A., Janke, A. M., Rhine, C. L. & Fawzi, N. L. Residue-by-residue view of in vitro FUS granules that bind the C-terminal domain of RNA polymerase II. Mol. Cell 60, 231–241 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Qamar, S. et al. FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation–pi interactions. Cell 173, 720–734.e15 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ray, S. et al. α-Synuclein aggregation nucleates through liquid–liquid phase separation. Nat. Chem. 12, 705–716 (2020).

    Article  CAS  PubMed  Google Scholar 

  84. Wegmann, S. et al. Tau protein liquid–liquid phase separation can initiate tau aggregation. EMBO J. 37, e98049 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Niaki, A. G. et al. Loss of dynamic RNA interaction and aberrant phase separation induced by two distinct types of ALS/FTD-linked FUS mutations. Mol. Cell 77, 82–94 (2020).

    Article  CAS  PubMed  Google Scholar 

  86. Kim, T. H. et al. Phospho-dependent phase separation of FMRP and CAPRIN1 recapitulates regulation of translation and deadenylation. Science 365, 825–829 (2019).

    Article  CAS  PubMed  Google Scholar 

  87. Gibson, B. A. et al. Organization of chromatin by intrinsic and regulated phase separation. Cell 179, 470–484.e21 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Maharana, S. et al. RNA buffers the phase separation behavior of prion-like RNA binding proteins. Science 360, 918–921 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Patel, A. et al. ATP as a biological hydrotrope. Science 356, 753–756 (2017).

    Article  CAS  PubMed  Google Scholar 

  90. Alberti, S. & Hyman, A. A. Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing. Nat. Rev. Mol. Cell Biol. 22, 196–213 (2021).

    Article  CAS  PubMed  Google Scholar 

  91. Hondele, M. et al. DEAD-box ATPases are global regulators of phase-separated organelles. Nature 573, 144–148 (2019).

    Article  CAS  PubMed  Google Scholar 

  92. Jang, S. et al. Glycolytic enzymes localize to synapses under energy stress to support synaptic function. Neuron 90, 278–291 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Jang, S. et al. Phosphofructokinase relocalizes into subcellular compartments with liquid-like properties in vivo. Biophys. J. 120, 1170–1186 (2021).

    Article  CAS  PubMed  Google Scholar 

  94. Wu, H. & Fuxreiter, M. The structure and dynamics of higher-order assemblies: amyloids, signalosomes, and granules. Cell 165, 1055–1066 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Alberti, S. & Dormann, D. Liquid–liquid phase separation in disease. Annu Rev. Genet. 53, 171–194 (2019).

    Article  CAS  PubMed  Google Scholar 

  96. Patel, A. et al. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162, 1066–1077 (2015).

    Article  CAS  PubMed  Google Scholar 

  97. Molliex, A. et al. Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 163, 123–133 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Hardenberg, M. C. et al. Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies. J. Mol. Cell Biol. https://doi.org/10.1093/jmcb/mjaa075 (2021).

  99. Roden, C. & Gladfelter, A. S. RNA contributions to the form and function of biomolecular condensates. Nat. Rev. Mol. Cell Biol. 22, 183–195 (2021).

    Article  CAS  PubMed  Google Scholar 

  100. Marrone, L., Quamar, S., Mannini, B., St George-Hyslop, P. & Vendruscolo, M. P525L promotes the aggregation of FUS by altering its biochemical and biophysical properties. Science Matters https://sciencematters.io/articles/202004000008/info (2020).

  101. Markmiller, S. et al. Context-dependent and disease-specific diversity in protein interactions within stress granules. Cell 172, 590–604 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Yang, P. et al. G3BP1 is a tunable switch that triggers phase separation to assemble stress granules. Cell 181, 325–345 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Li, W. et al. Biophysical properties of AKAP95 protein condensates regulate splicing and tumorigenesis. Nat. Cell Biol. 22, 960–972 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Vendruscolo, M. & Fuxreiter, M. Sequence determinants of the aggregation of proteins within condensates generated by liquid-liquid phase separation. Preprint at BioRxiv https://doi.org/10.1101/2020.12.07.414409 (2020).

  105. Guo, L. et al. Nuclear-import receptors reverse aberrant phase transitions of RNA-binding proteins with prion-like domains. Cell 173, 677–692 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Heller, G. T. et al. Small-molecule sequestration of amyloid-beta as a drug discovery strategy for Alzheimer’s disease. Sci. Adv. 6, eabb5924 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Klein, I. A. et al. Partitioning of cancer therapeutics in nuclear condensates. Science 368, 1386–1392 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Song, H., Inaka, K., Maenaka, K. & Matsushima, M. Structural changes of active site cleft and different saccharide binding modes in human lysozyme co-crystallized with hexa-N-acetyl-chitohexaose at pH 4.0. J. Mol. Biol. 244, 522–540 (1994).

    Article  CAS  PubMed  Google Scholar 

  109. Huang, W. Y. C. et al. A molecular assembly phase transition and kinetic proofreading modulate Ras activation by SOS. Science 363, 1098–1103 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Nogales, E. An electron microscopy journey in the study of microtubule structure and dynamics. Protein Sci. 24, 1912–1919 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Huang, D. T. et al. Basis for a ubiquitin-like protein thioester switch toggling E1–E2 affinity. Nature 445, 394–398 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Park, J. E. et al. Phase separation of Polo-like kinase 4 by autoactivation and clustering drives centriole biogenesis. Nat. Commun. 10, 4959 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. 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).

    Article  CAS  PubMed  Google Scholar 

  114. Ciuffa, R. et al. The selective autophagy receptor p62 forms a flexible filamentous helical scaffold. Cell Rep. 11, 748–758 (2015).

    Article  CAS  PubMed  Google Scholar 

  115. Song, H. & Ji, X. The mechanism of RNA duplex recognition and unwinding by DEAD-box helicase DDX3X. Nat. Commun. 10, 3085 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Gross, J. D. et al. Ribosome loading onto the mRNA cap is driven by conformational coupling between eIF4G and eIF4E. Cell 115, 739–750 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Cao, Q., Boyer, D. R., Sawaya, M. R., Ge, P. & Eisenberg, D. S. Cryo-EM structures of four polymorphic TDP-43 amyloid cores. Nat. Struct. Mol. Biol. 26, 619–627 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Department of Biomedical Sciences, University of Padova, Padova, Italy

    Monika Fuxreiter

  2. Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary

    Monika Fuxreiter

  3. Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, UK

    Michele Vendruscolo

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Fuxreiter, M., Vendruscolo, M. Generic nature of the condensed states of proteins. Nat Cell Biol 23, 587–594 (2021). https://doi.org/10.1038/s41556-021-00697-8

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