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Liquid–liquid phase separation as an organizing principle of intracellular space: overview of the evolution of the cell compartmentalization concept

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Abstract

At the turn of the twenty-first century, fundamental changes took place in the understanding of the structure and function of proteins and then in the appreciation of the intracellular space organization. A rather mechanistic model of the organization of living matter, where the function of proteins is determined by their rigid globular structure, and the intracellular processes occur in rigidly determined compartments, was replaced by an idea that highly dynamic and multifunctional "soft matter" lies at the heart of all living things. According this “new view”, the most important role in the spatio-temporal organization of the intracellular space is played by liquid–liquid phase transitions of biopolymers. These self-organizing cellular compartments are open dynamic systems existing at the edge of chaos. They are characterized by the exceptional structural and compositional dynamics, and their multicomponent nature and polyfunctionality provide means for the finely tuned regulation of various intracellular processes. Changes in the external conditions can cause a disruption of the biogenesis of these cellular bodies leading to the irreversible aggregation of their constituent proteins, followed by the transition to a gel-like state and the emergence of amyloid fibrils. This work represents a historical overview of changes in our understanding of the intracellular space compartmentalization. It also reflects methodological breakthroughs that led to a change in paradigms in this area of science and discusses modern ideas about the organization of the intracellular space. It is emphasized here that the membrane-less organelles have to combine a certain resistance to the changes in their environment and, at the same time, show high sensitivity to the external signals, which ensures the normal functioning of the cell.

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References

  1. Meyer H (1899) Zur theorie der alkoholnarkose. Archiv für experimentelle Pathologie und Pharmakologie 42(2–4):109–118

    Google Scholar 

  2. Overton CE (1901) Studien über die Narkose: zugleich ein Beitrag zur allgemeinen Pharmakologie. G. Fischer, Jena

    Google Scholar 

  3. Missner A, Pohl P (2009) 110 years of the Meyer-Overton rule: predicting membrane permeability of gases and other small compounds. ChemPhysChem 10(9–10):1405–1414. https://doi.org/10.1002/cphc.200900270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hannesschlaeger C, Horner A, Pohl P (2019) Intrinsic membrane permeability to small molecules. Chem Rev 119(9):5922–5953. https://doi.org/10.1021/acs.chemrev.8b00560

    Article  CAS  PubMed  Google Scholar 

  5. Peracchia C (ed) (1994) Handbook of membrane channels molecular and cellular physiology. Academic Press, London

    Google Scholar 

  6. Pederson T (2011) The nucleoulus. Cold Spring Harb Perspect Biol 3(3):a000638. https://doi.org/10.1101/cshperspect.a000638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Uversky VN (2019) Protein intrinsic disorder and structure-function continuum. Prog Mol Biol Transl Sci 166:1–17. https://doi.org/10.1016/bs.pmbts.2019.05.003

    Article  CAS  PubMed  Google Scholar 

  8. Fonin AV, Darling AL, Kuznetsova IM, Turoverov KK, Uversky VN (2019) Multi-functionality of proteins involved in GPCR and G protein signaling: making sense of structure-function continuum with intrinsic disorder-based proteoforms. Cell Mol Life Sci 76(22):4461–4492. https://doi.org/10.1007/s00018-019-03276-1

    Article  CAS  PubMed  Google Scholar 

  9. Uversky VN (2016) p53 proteoforms and intrinsic disorder: an illustration of the protein structure-function continuum concept. Int J Mol Sci. https://doi.org/10.3390/ijms17111874

    Article  PubMed  PubMed Central  Google Scholar 

  10. Cate JH, Yusupov MM, Yusupova GZ, Earnest TN, Noller HF (1999) X-ray crystal structures of 70S ribosome functional complexes. Science 285(5436):2095–2104. https://doi.org/10.1126/science.285.5436.2095

    Article  CAS  PubMed  Google Scholar 

  11. Yusupov MM, Yusupova GZ, Baucom A, Lieberman K, Earnest TN, Cate JH, Noller HF (2001) Crystal structure of the ribosome at 5.5 A resolution. Science 292(5518):883–896. https://doi.org/10.1126/science.1060089

    Article  CAS  PubMed  Google Scholar 

  12. Ben-Shem A, Garreau de Loubresse N, Melnikov S, Jenner L, Yusupova G, Yusupov M (2011) The structure of the eukaryotic ribosome at 3.0 A resolution. Science 334(6062):1524–1529. https://doi.org/10.1126/science.1212642

    Article  CAS  PubMed  Google Scholar 

  13. Yusupova G, Yusupov M (2021) A path to the atomic-resolution structures of prokaryotic and eukaryotic ribosomes. Biochemistry (Mosc) 86(8):926–941. https://doi.org/10.1134/S0006297921080046

    Article  CAS  Google Scholar 

  14. Peng Z, Oldfield CJ, Xue B, Mizianty MJ, Dunker AK, Kurgan L, Uversky VN (2014) A creature with a hundred waggly tails: intrinsically disordered proteins in the ribosome. Cell Mol Life Sci 71(8):1477–1504. https://doi.org/10.1007/s00018-013-1446-6

    Article  CAS  PubMed  Google Scholar 

  15. Hooke R (1665) Micrographia: or some physiological descriptions of minute bodies made by magnifying glasses with observations and inquiries thereupon. J. Martyn and J. Allestry, London

  16. Van Leeuwenhoek A (1677) Observations, communicated to the publisher by Mr. Antony van Leewenhoeck, in a dutch letter of the 9th Octob. 1676. here English'd: concerning little animals by him observed in rain-well-sea- and snow water; as also in water wherein pepper had lain infused. Philos Trans 12 (133):821-831. doi: https://doi.org/10.1098/rstl.1677.0003

    Article  Google Scholar 

  17. Schliwa M (2002) The evolving complexity of cytoplasmic structure. Nat Rev Mol Cell Biol 3(4):291–296. https://doi.org/10.1038/nrm781

    Article  CAS  PubMed  Google Scholar 

  18. Schleiden MJ (1838) Beiträge zur Phytogenesis. Archiv für Anatomie, Physiologie und wissenschaftliche Medicin. Veit, Berlin

  19. Schwann T (1839) Mikroscopische Untersuchungen über die Übereinstimmung in der Struktur und dem Wachsthum der Tiere und Pflanzen. Reimer, Berlin

    Google Scholar 

  20. Wagner R (1835) Einige bemerkungen und fragen über das keimbläschen (vesicular germinativa). Müller’s Archiv Anat Physiol Wissenschaft Med 268:373–377

    Google Scholar 

  21. Valentin G (1837) Repertorium für anatomie und physiologie: kritische darstellung fremder und ergebnisse eigener forschung. Verlag von Veit und Comp, Berlin

    Google Scholar 

  22. Brown R (1866) On the organs and mode of fecundation of orchidex and asclepiadea. In: Bennett JJ (ed) Miscellaneous botanical works of Robert Brown, vol 1. Publisher for the Ray society by R. Hardwicke, London, pp 511–514. https://doi.org/10.5962/bhl.title.21295

    Chapter  Google Scholar 

  23. Purkinje JE (1839) ‘Uber die Analogieen in den Struktur-Elementen des thierischen und pflanzlichen Organismus. Ûbersicht der Arbeiten und Verånderungen der Schlesischen Gesellschaft fçr Vaterlåndische Cultur im Jahre, pp 81–82

  24. Welch GR, Clegg JS (2012) Cell versus protoplasm: revisionist history. Cell Biol Int 36(7):643–647. https://doi.org/10.1042/CBI20120128

    Article  PubMed  Google Scholar 

  25. Flemming W (1879) Beitrage zur Kenntniss der Zelle und ihrer Lebenserscheinungen. Arch Mikrosk Anat 16:302–436

    Article  Google Scholar 

  26. Raspail PM (1830) Essai de chimie microscopique appliquée à la physiologie, ou L’art de transporter le laboratoire sur le porte-objet dans l’étude des corps organisés. L’auteur, Paris

    Google Scholar 

  27. Wilson EB (1899) The structure of protoplasm. Science 10(237):33–45. https://doi.org/10.1126/science.10.237.33

    Article  CAS  PubMed  Google Scholar 

  28. Brangwynne CP, Eckmann CR, Courson DS, Rybarska A, Hoege C, Gharakhani J, Julicher F, Hyman AA (2009) Germline P granules are liquid droplets that localize by controlled dissolution/condensation. Science 324(5935):1729–1732. https://doi.org/10.1126/science.1172046

    Article  CAS  PubMed  Google Scholar 

  29. Oparin AI (1924) The origine of Life. Moscow Worker, Moscow

    Google Scholar 

  30. Tirard S (2017) J. B. S. Haldane and the origin of life. J Genet 96(5):735–739. https://doi.org/10.1007/s12041-017-0831-6

    Article  PubMed  Google Scholar 

  31. Haldane JBS (1929) The origin of life Rationalist Annual 148:3–10

    Google Scholar 

  32. Overbeek JT, Voorn MJ (1957) Phase separation in polyelectrolyte solutions; theory of complex coacervation. J Cell Physiol Suppl 49(Suppl 1):7–22 (discussion, 22-26)

    Article  CAS  PubMed  Google Scholar 

  33. McMullen JN, Newton DW, Becker CH (1982) Pectin-gelatin complex coacervates I: determinants of microglobule size, morphology, and recovery as water-dispersible powders. J Pharm Sci 71(6):628–633. https://doi.org/10.1002/jps.2600710608

    Article  CAS  PubMed  Google Scholar 

  34. Jizomoto H (1984) Phase separation induced in gelatin-base coacervation systems by addition of water-soluble nonionic polymers I: Microencapsulation. J Pharm Sci 73(7):879–882. https://doi.org/10.1002/jps.2600730705

    Article  CAS  PubMed  Google Scholar 

  35. Yu S, Hu J, Pan X, Yao P, Jiang M (2006) Stable and pH-sensitive nanogels prepared by self-assembly of chitosan and ovalbumin. Langmuir 22(6):2754–2759. https://doi.org/10.1021/la053158b

    Article  CAS  PubMed  Google Scholar 

  36. Sarmento B, Ribeiro A, Veiga F, Sampaio P, Neufeld R, Ferreira D (2007) Alginate/chitosan nanoparticles are effective for oral insulin delivery. Pharm Res 24(12):2198–2206. https://doi.org/10.1007/s11095-007-9367-4

    Article  CAS  PubMed  Google Scholar 

  37. Izmailova VN, Rebinder PA (1974) Structure formation in protein systems. Science (Nauka), Moscow

    Google Scholar 

  38. Robertson JD (1957) New observations on the ultrastructure of the membranes of frog peripheral nerve fibers. J Biophys Biochem Cytol 3(6):1043–1048. https://doi.org/10.1083/jcb.3.6.1043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gorter E, Grendel F (1925) On Bimolecular layers of lipoids on the chromocytes of the blood. J Exp Med 41(4):439–443. https://doi.org/10.1084/jem.41.4.439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Palade GE (1952) The fine structure of mitochondria. Anat Rec 114(3):427–451. https://doi.org/10.1002/ar.1091140304

    Article  CAS  PubMed  Google Scholar 

  41. Palade GE, Porter KR (1954) Studies on the endoplasmic reticulum. I. Its identification in cells in situ. J Exp Med 100(6):641–656. https://doi.org/10.1084/jem.100.6.641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dalton AJ, Felix MD (1954) Cytologic and cytochemical characteristics of the Golgi substance of epithelial cells of the epididymis in situ, in homogenates and after isolation. Am J Anat 94(2):171–207. https://doi.org/10.1002/aja.1000940202

    Article  CAS  PubMed  Google Scholar 

  43. Singer SJ (1970) Biochemical organization of cell membranes. Birth Defects Orig Artic Ser 6(3):15–16

    CAS  PubMed  Google Scholar 

  44. Singer SJ (1974) The molecular organization of membranes. Annu Rev Biochem 43:805–833. https://doi.org/10.1146/annurev.bi.43.070174.004105

    Article  CAS  PubMed  Google Scholar 

  45. Singer SJ (1981) Current concepts of molecular organization in cell membranes. Biochem Soc Trans 9(3):203–206. https://doi.org/10.1042/bst0090203

    Article  CAS  PubMed  Google Scholar 

  46. Overton CE (1895) Über die osmotischen Eigenschaften der lebenden Pflanzen-und Tierzelle. Fäsi & Beer, Zürich

    Google Scholar 

  47. Sigworth FJ, Neher E (1980) Single Na+ channel currents observed in cultured rat muscle cells. Nature 287(5781):447–449. https://doi.org/10.1038/287447a0

    Article  CAS  PubMed  Google Scholar 

  48. Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflug Arch 391(2):85–100. https://doi.org/10.1007/BF00656997

    Article  CAS  Google Scholar 

  49. Sakmann B, Neher E (1984) Patch clamp techniques for studying ionic channels in excitable membranes. Annu Rev Physiol 46:455–472. https://doi.org/10.1146/annurev.ph.46.030184.002323

    Article  CAS  PubMed  Google Scholar 

  50. Mueller P, Rudin DO, Tien HT, Wescott WC (1962) Reconstitution of cell membrane structure in vitro and its transformation into an excitable system. Nature 194:979–980. https://doi.org/10.1038/194979a0

    Article  CAS  PubMed  Google Scholar 

  51. Watson H (2015) Biological membranes. Essays Biochem 59:43–69. https://doi.org/10.1042/bse0590043

    Article  PubMed  PubMed Central  Google Scholar 

  52. Skou JC (1957) The influence of some cations on an adenosine triphosphatase from peripheral nerves. Biochim Biophys Acta 23(2):394–401. https://doi.org/10.1016/0006-3002(57)90343-8

    Article  CAS  PubMed  Google Scholar 

  53. Skou JC (1962) Preparation from mammallian brain and kidney of the enzyme system involved in active transport of Na ions and K ions. Biochim Biophys Acta 58:314–325. https://doi.org/10.1016/0006-3002(62)91015-6

    Article  CAS  PubMed  Google Scholar 

  54. Hyman T, Brangwynne CP (2012) In retrospect: the origin of life. Nature 491:524–525

    Article  CAS  Google Scholar 

  55. Franklin RE, Gosling RG (1953) Molecular configuration in sodium thymonucleate. Nature 171(4356):740–741. https://doi.org/10.1038/171740a0

    Article  CAS  PubMed  Google Scholar 

  56. Wilkins MH, Stokes AR, Wilson HR (1953) Molecular structure of deoxypentose nucleic acids. Nature 171(4356):738–740. https://doi.org/10.1038/171738a0

    Article  CAS  PubMed  Google Scholar 

  57. Watson JD, Crick FH (1953) Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature 171(4356):737–738. https://doi.org/10.1038/171737a0

    Article  CAS  PubMed  Google Scholar 

  58. Perutz MF, Rossmann MG, Cullis AF, Muirhead H, Will G, North AC (1960) Structure of haemoglobin: a three-dimensional Fourier synthesis at 5.5-A. Resolution, obtained by X-ray analysis. Nature 185(4711):416–422. https://doi.org/10.1038/185416a0

    Article  CAS  PubMed  Google Scholar 

  59. Kendrew JC, Bodo G, Dintzis HM, Parrish RG, Wyckoff H, Phillips DC (1958) A three-dimensional model of the myoglobin molecule obtained by x-ray analysis. Nature 181(4610):662–666. https://doi.org/10.1038/181662a0

    Article  CAS  PubMed  Google Scholar 

  60. Anfinsen CB (1973) Principles that govern the folding of protein chains. Science 181(4096):223–230. https://doi.org/10.1126/science.181.4096.223

    Article  CAS  PubMed  Google Scholar 

  61. Crowther RA, Klug A (1975) Structural analysis of macromolecular assemblies by image reconstruction from electron micrographs. Annu Rev Biochem 44:161–182. https://doi.org/10.1146/annurev.bi.44.070175.001113

    Article  CAS  PubMed  Google Scholar 

  62. Deisenhofer J, Epp O, Miki K, Huber R, Michel H (1984) X-ray structure analysis of a membrane protein complex. Electron density map at 3 A resolution and a model of the chromophores of the photosynthetic reaction center from Rhodopseudomonas viridis. J Mol Biol 180(2):385–398. https://doi.org/10.1016/s0022-2836(84)80011-x

    Article  CAS  PubMed  Google Scholar 

  63. Preston GM, Carroll TP, Guggino WB, Agre P (1992) Appearance of water channels in Xenopus oocytes expressing red cell CHIP28 protein. Science 256(5055):385–387. https://doi.org/10.1126/science.256.5055.385

    Article  CAS  PubMed  Google Scholar 

  64. Doyle DA, Morais Cabral J, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT, MacKinnon R (1998) The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280(5360):69–77. https://doi.org/10.1126/science.280.5360.69

    Article  CAS  PubMed  Google Scholar 

  65. Michaelis L, Menten ML (1913) “Die Kinetik der Invertinwirkung” [The kinetics of invertin action]. Biochem Z 49(17):333–369

    CAS  Google Scholar 

  66. Henri V (2006) Théorie générale de l’action de quelques diastases par Victor Henri [CR Acad. Sci. Paris 135 (1902) 916-919]. Comptes Rendus Biol 329(1):47–50

    Article  Google Scholar 

  67. Fischer E (1894) Einfluss der configuration auf die wirkung der enzyme. Ber Dt Chem Ges 27:2985–2993

    Article  CAS  Google Scholar 

  68. Koshland DE Jr (1958) Application of a theory of enzyme specificity to protein synthesis. Proc Natl Acad Sci USA 44:98–104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Straub FB, Szabolcsi G (1964) O dinamicseszkih aszpektah sztukturü fermentov (On the dynamic aspects of protein structure). In: Braunstein AE (ed) Molecular biology, problems and perspectives. Nauka, pp 182–187

    Google Scholar 

  70. Monod J, Wyman J, Changeux JP (1965) On the nature of allosteric transitions: a plausible model. J Mol Biol 12:88–118. https://doi.org/10.1016/s0022-2836(65)80285-6

    Article  CAS  PubMed  Google Scholar 

  71. Koshland DE Jr, Nemethy G, Filmer D (1966) Comparison of experimental binding data and theoretical models in proteins containing subunits. Biochemistry 5(1):365–385. https://doi.org/10.1021/bi00865a047

    Article  CAS  PubMed  Google Scholar 

  72. Burgen AS (1981) Conformational changes and drug action. Fed Proc 40(13):2723–2728

    CAS  PubMed  Google Scholar 

  73. Gronenborn AM, Clore GM, Blazy B, Baudras A (1981) Conformational selection of syn-cAMP upon binding to the cAMP: receptor protein. FEBS Lett 136(1):160–164. https://doi.org/10.1016/0014-5793(81)81237-9

    Article  CAS  PubMed  Google Scholar 

  74. Sedzik J, Kirschner DA (1992) Is myelin basic protein crystallizable? Neurochem Res 17(2):157–166. https://doi.org/10.1007/BF00966794

    Article  CAS  PubMed  Google Scholar 

  75. Yasuzumi G, Sawada T, Sugihara R, Kiriyama M, Sugioka M (1958) Electron microscope researches on the ultrastructure of nucleoli in animal tissues. Z Zellforsch Mikrosk Anat 48(1):10–23. https://doi.org/10.1007/BF00496710

    Article  CAS  PubMed  Google Scholar 

  76. Schofer C, Weipoltshammer K (2018) Nucleolus and chromatin. Histochem Cell Biol 150(3):209–225. https://doi.org/10.1007/s00418-018-1696-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Monneron A, Bernhard W (1969) Fine structural organization of the interphase nucleus in some mammalian cells. J Ultrastruct Res 27(3):266–288. https://doi.org/10.1016/s0022-5320(69)80017-1

    Article  CAS  PubMed  Google Scholar 

  78. Cajal SR (1903) Un sencillo metodo de coloracion selectiva del reticulo protoplasmico y sus efectos en los diversos organos nerviosos de vertebrados e invertebrados. Trab Lab Investig Biol Univ Madr 2:129–221

    Google Scholar 

  79. Cajal SR (1903) Un sencillo metodo de coloracion seletiva del reticulo protoplasmatico y sus efectos en los diversos organos nerviosos de vertebrados e invertebrados. Trab Lab Invest Biol(Madrid) 2:129–221

    Google Scholar 

  80. Morris GE (2008) The Cajal body. Biochim Biophys Acta 1783(11):2108–2115. https://doi.org/10.1016/j.bbamcr.2008.07.016

    Article  CAS  PubMed  Google Scholar 

  81. Alberti S (2017) Phase separation in biology. Curr Biol 27(20):R1097–R1102. https://doi.org/10.1016/j.cub.2017.08.069

    Article  CAS  PubMed  Google Scholar 

  82. Dunker AK, Lawson JD, Brown CJ, Williams RM, Romero P, Oh JS, Oldfield CJ, Campen AM, Ratliff CM, Hipps KW, Ausio J, Nissen MS, Reeves R, Kang C, Kissinger CR, Bailey RW, Griswold MD, Chiu W, Garner EC, Obradovic Z (2001) Intrinsically disordered protein. J Mol Graph Model 19(1):26–59. https://doi.org/10.1016/s1093-3263(00)00138-8

    Article  CAS  PubMed  Google Scholar 

  83. Uversky VN, Gillespie JR, Fink AL (2000) Why are “natively unfolded” proteins unstructured under physiologic conditions? Proteins 41(3):415–427. https://doi.org/10.1002/1097-0134(20001115)41:3%3c415::aid-prot130%3e3.0.co;2-7

    Article  CAS  PubMed  Google Scholar 

  84. Wright PE, Dyson HJ (1999) Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm. J Mol Biol 293(2):321–331. https://doi.org/10.1006/jmbi.1999.3110

    Article  CAS  PubMed  Google Scholar 

  85. Oldfield CJ, Cheng Y, Cortese MS, Brown CJ, Uversky VN, Dunker AK (2005) Comparing and combining predictors of mostly disordered proteins. Biochemistry 44(6):1989–2000. https://doi.org/10.1021/bi047993o

    Article  CAS  PubMed  Google Scholar 

  86. van der Lee R, Buljan M, Lang B, Weatheritt RJ, Daughdrill GW, Dunker AK, Fuxreiter M, Gough J, Gsponer J, Jones DT, Kim PM, Kriwacki RW, Oldfield CJ, Pappu RV, Tompa P, Uversky VN, Wright PE, Babu MM (2014) Classification of intrinsically disordered regions and proteins. Chem Rev 114(13):6589–6631. https://doi.org/10.1021/cr400525m

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Oldfield CJ, Dunker AK (2014) Intrinsically disordered proteins and intrinsically disordered protein regions. Annu Rev Biochem 83:553–584. https://doi.org/10.1146/annurev-biochem-072711-164947

    Article  CAS  PubMed  Google Scholar 

  88. Uversky VN, Dunker AK (2010) Understanding protein non-folding. Biochim Biophys Acta 1804(6):1231–1264. https://doi.org/10.1016/j.bbapap.2010.01.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Dunker AK, Silman I, Uversky VN, Sussman JL (2008) Function and structure of inherently disordered proteins. Curr Opin Struct Biol 18(6):756–764. https://doi.org/10.1016/j.sbi.2008.10.002

    Article  CAS  PubMed  Google Scholar 

  90. Uversky VN, Oldfield CJ, Dunker AK (2005) Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling. J Mol Recognit 18(5):343–384. https://doi.org/10.1002/jmr.747

    Article  CAS  PubMed  Google Scholar 

  91. Tompa P (2005) The interplay between structure and function in intrinsically unstructured proteins. FEBS Lett 579(15):3346–3354. https://doi.org/10.1016/j.febslet.2005.03.072

    Article  CAS  PubMed  Google Scholar 

  92. Dyson HJ, Wright PE (2005) Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol 6(3):197–208. https://doi.org/10.1038/nrm1589

    Article  CAS  PubMed  Google Scholar 

  93. Uversky VN (2003) Protein folding revisited. A polypeptide chain at the folding-misfolding-nonfolding cross-roads: which way to go? Cell Mol Life Sci 60(9):1852–1871. https://doi.org/10.1007/s00018-003-3096-6

    Article  CAS  PubMed  Google Scholar 

  94. Tompa P (2002) Intrinsically unstructured proteins. Trends Biochem Sci 27(10):527–533. https://doi.org/10.1016/s0968-0004(02)02169-2

    Article  CAS  PubMed  Google Scholar 

  95. Uversky VN (2002) Natively unfolded proteins: a point where biology waits for physics. Protein Sci 11(4):739–756. https://doi.org/10.1110/ps.4210102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Uversky VN (2002) What does it mean to be natively unfolded? Eur J Biochem 269(1):2–12. https://doi.org/10.1046/j.0014-2956.2001.02649.x

    Article  CAS  PubMed  Google Scholar 

  97. Dunker AK, Obradovic Z (2001) The protein trinity–linking function and disorder. Nat Biotechnol 19(9):805–806. https://doi.org/10.1038/nbt0901-805

    Article  CAS  PubMed  Google Scholar 

  98. Hu G, Wu Z, Uversky VN, Kurgan L (2017) Functional analysis of human hub proteins and their interactors involved in the intrinsic disorder-enriched interactions. Int J Mol Sci. https://doi.org/10.3390/ijms18122761

    Article  PubMed  PubMed Central  Google Scholar 

  99. Oldfield CJ, Meng J, Yang JY, Yang MQ, Uversky VN, Dunker AK (2008) Flexible nets: disorder and induced fit in the associations of p53 and 14–3-3 with their partners. BMC Genom 9(Suppl 1):S1. https://doi.org/10.1186/1471-2164-9-S1-S1

    Article  CAS  Google Scholar 

  100. Dosztanyi Z, Chen J, Dunker AK, Simon I, Tompa P (2006) Disorder and sequence repeats in hub proteins and their implications for network evolution. J Proteome Res 5(11):2985–2995. https://doi.org/10.1021/pr060171o

    Article  CAS  PubMed  Google Scholar 

  101. Haynes C, Oldfield CJ, Ji F, Klitgord N, Cusick ME, Radivojac P, Uversky VN, Vidal M, Iakoucheva LM (2006) Intrinsic disorder is a common feature of hub proteins from four eukaryotic interactomes. PLoS Comput Biol 2(8):e100. https://doi.org/10.1371/journal.pcbi.0020100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN (2005) Flexible nets. The roles of intrinsic disorder in protein interaction networks. FEBS J 272(20):5129–5148. https://doi.org/10.1111/j.1742-4658.2005.04948.x

    Article  CAS  PubMed  Google Scholar 

  103. Dunker AK, Brown CJ, Obradovic Z (2002) Identification and functions of usefully disordered proteins. Adv Protein Chem 62:25–49. https://doi.org/10.1016/s0065-3233(02)62004-2

    Article  CAS  PubMed  Google Scholar 

  104. Iakoucheva LM, Brown CJ, Lawson JD, Obradovic Z, Dunker AK (2002) Intrinsic disorder in cell-signaling and cancer-associated proteins. J Mol Biol 323(3):573–584. https://doi.org/10.1016/s0022-2836(02)00969-5

    Article  CAS  PubMed  Google Scholar 

  105. Dunker AK, Brown CJ, Lawson JD, Iakoucheva LM, Obradovic Z (2002) Intrinsic disorder and protein function. Biochemistry 41(21):6573–6582. https://doi.org/10.1021/bi012159+

    Article  CAS  PubMed  Google Scholar 

  106. Dyson HJ, Wright PE (2002) Coupling of folding and binding for unstructured proteins. Curr Opin Struct Biol 12(1):54–60. https://doi.org/10.1016/s0959-440x(02)00289-0

    Article  CAS  PubMed  Google Scholar 

  107. Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN (2005) Flexible nets: the roles of intrinsic disorder in protein interaction networks. FEBS J 272(20):5129–5148. https://doi.org/10.1111/j.1742-4658.2005.04948.x

    Article  CAS  PubMed  Google Scholar 

  108. Cortese MS, Uversky VN, Dunker AK (2008) Intrinsic disorder in scaffold proteins: getting more from less. Prog Biophys Mol Biol 98(1):85–106. https://doi.org/10.1016/j.pbiomolbio.2008.05.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Dunker AK, Uversky VN (2008) Signal transduction via unstructured protein conduits. Nat Chem Biol 4(4):229–230. https://doi.org/10.1038/nchembio0408-229

    Article  CAS  PubMed  Google Scholar 

  110. Dunker AK, Oldfield CJ, Meng J, Romero P, Yang JY, Chen JW, Vacic V, Obradovic Z, Uversky VN (2008) The unfoldomics decade: an update on intrinsically disordered proteins. BMC Genom 9(Suppl 2):S1. https://doi.org/10.1186/1471-2164-9-S2-S1

    Article  Google Scholar 

  111. Uversky VN, Dunker AK (2010) Understanding protein non-folding. Bba-Proteins Proteom 1804(6):1231–1264. https://doi.org/10.1016/j.bbapap.2010.01.017

    Article  CAS  Google Scholar 

  112. Uversky VN, Li J, Fink AL (2001) Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein. A possible molecular NK between Parkinson’s disease and heavy metal exposure. J Biol Chem 276(47):44284–44296

    Article  CAS  PubMed  Google Scholar 

  113. Uversky VN, Permyakov SE, Zagranichny VE, Rodionov IL, Fink AL, Cherskaya AM, Wasserman LA, Permyakov EA (2002) Effect of zinc and temperature on the conformation of the gamma subunit of retinal phosphodiesterase: a natively unfolded protein. J Proteome Res 1(2):149–159

    Article  CAS  PubMed  Google Scholar 

  114. Venyaminov SY, Gudkov AT, Gogia ZV, Tumanova LG (1981) Absorption and circular dichroism spectra of individual proteins from Escherichia coli ribosomes. American Chemical Society, Pushchino, Russia

  115. Craig TA, Veenstra TD, Naylor S, Tomlinson AJ, Johnson KL, Macura S, Juranic N, Kumar R (1997) Zinc binding properties of the DNA binding domain of the 1,25-dihydroxyvitamin D3 receptor. Biochemistry 36(34):10482–10491

    Article  CAS  PubMed  Google Scholar 

  116. Rice LM, Brennwald P, Brunger AT (1997) Formation of a yeast SNARE complex is accompanied by significant structural changes. FEBS Lett 415(1):49–55

    Article  CAS  PubMed  Google Scholar 

  117. Permyakov SE, Millett IS, Doniach S, Permyakov EA, Uversky VN (2003) Natively unfolded C-terminal domain of caldesmon remains substantially unstructured after the effective binding to calmodulin. Proteins 53(4):855–862

    Article  CAS  PubMed  Google Scholar 

  118. Fink AL (2005) Natively unfolded proteins. Curr Opin Struct Biol 15(1):35–41

    Article  CAS  PubMed  Google Scholar 

  119. Peng Z, Mizianty MJ, Xue B, Kurgan L, Uversky VN (2012) More than just tails: intrinsic disorder in histone proteins. Mol Biosyst 8(7):1886–1901. https://doi.org/10.1039/c2mb25102g

    Article  CAS  PubMed  Google Scholar 

  120. Cheng Y, Oldfield CJ, Meng J, Romero P, Uversky VN, Dunker AK (2007) Mining alpha-helix-forming molecular recognition features with cross species sequence alignments. Biochemistry 46(47):13468–13477. https://doi.org/10.1021/bi7012273

    Article  CAS  PubMed  Google Scholar 

  121. Vacic V, Oldfield CJ, Mohan A, Radivojac P, Cortese MS, Uversky VN, Dunker AK (2007) Characterization of molecular recognition features, MoRFs, and their binding partners. J Proteome Res 6(6):2351–2366. https://doi.org/10.1021/pr0701411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Mohan A, Oldfield CJ, Radivojac P, Vacic V, Cortese MS, Dunker AK, Uversky VN (2006) Analysis of molecular recognition features (MoRFs). J Mol Biol 362(5):1043–1059. https://doi.org/10.1016/j.jmb.2006.07.087

    Article  CAS  PubMed  Google Scholar 

  123. Oldfield CJ, Cheng Y, Cortese MS, Romero P, Uversky VN, Dunker AK (2005) Coupled folding and binding with alpha-helix-forming molecular recognition elements. Biochemistry 44(37):12454–12470. https://doi.org/10.1021/bi050736e

    Article  CAS  PubMed  Google Scholar 

  124. Uversky VN (2011) Multitude of binding modes attainable by intrinsically disordered proteins: a portrait gallery of disorder-based complexes. Chem Soc Rev 40(3):1623–1634. https://doi.org/10.1039/c0cs00057d

    Article  CAS  PubMed  Google Scholar 

  125. Tompa P, Fuxreiter M (2008) Fuzzy complexes: polymorphism and structural disorder in protein-protein interactions. Trends Biochem Sci 33(1):2–8. https://doi.org/10.1016/j.tibs.2007.10.003

    Article  CAS  PubMed  Google Scholar 

  126. Fuxreiter M (2018) Towards a stochastic paradigm: from fuzzy ensembles to cellular functions. Molecules 23(11):3008. https://doi.org/10.3390/molecules23113008

    Article  CAS  PubMed Central  Google Scholar 

  127. Miskei M, Gregus A, Sharma R, Duro N, Zsolyomi F, Fuxreiter M (2017) Fuzziness enables context dependence of protein interactions. FEBS Lett 591(17):2682–2695. https://doi.org/10.1002/1873-3468.12762

    Article  CAS  PubMed  Google Scholar 

  128. Gruet A, Dosnon M, Blocquel D, Brunel J, Gerlier D, Das RK, Bonetti D, Gianni S, Fuxreiter M, Longhi S, Bignon C (2016) Fuzzy regions in an intrinsically disordered protein impair protein-protein interactions. FEBS J 283(4):576–594. https://doi.org/10.1111/febs.13631

    Article  CAS  PubMed  Google Scholar 

  129. Sharma R, Raduly Z, Miskei M, Fuxreiter M (2015) Fuzzy complexes: Specific binding without complete folding. FEBS Lett 589(19 Pt A):2533–2542. https://doi.org/10.1016/j.febslet.2015.07.022

    Article  CAS  PubMed  Google Scholar 

  130. Fuxreiter M, Tompa P (2012) Fuzzy complexes: a more stochastic view of protein function. Adv Exp Med Biol 725:1–14. https://doi.org/10.1007/978-1-4614-0659-4_1

    Article  CAS  PubMed  Google Scholar 

  131. Fuxreiter M (2012) Fuzziness: linking regulation to protein dynamics. Mol Biosyst 8(1):168–177. https://doi.org/10.1039/c1mb05234a

    Article  CAS  PubMed  Google Scholar 

  132. Alterovitz WL, Faraggi E, Oldfield CJ, Meng J, Xue B, Huang F, Romero P, Kloczkowski A, Uversky VN, Dunker AK (2020) Many-to-one binding by intrinsically disordered protein regions. Pac Symp Biocomput 25:159–170

    PubMed  Google Scholar 

  133. Borgia A, Borgia MB, Bugge K, Kissling VM, Heidarsson PO, Fernandes CB, Sottini A, Soranno A, Buholzer KJ, Nettels D, Kragelund BB, Best RB, Schuler B (2018) Extreme disorder in an ultrahigh-affinity protein complex. Nature 555(7694):61–66. https://doi.org/10.1038/nature25762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Uversky VN (2009) Intrinsic disorder in proteins associated with neurodegenerative diseases. Front Biosci (Landmark Ed) 14:5188–5238. https://doi.org/10.2741/3594

    Article  CAS  Google Scholar 

  135. Uversky VN (2014) The triple power of D(3): protein intrinsic disorder in degenerative diseases. Front Biosci (Landmark Ed) 19:181–258. https://doi.org/10.2741/4204

    Article  CAS  Google Scholar 

  136. Uversky VN (2010) Targeting intrinsically disordered proteins in neurodegenerative and protein dysfunction diseases: another illustration of the D(2) concept. Expert Rev Proteom 7(4):543–564. https://doi.org/10.1586/epr.10.36

    Article  CAS  Google Scholar 

  137. Uversky VN (2010) Mysterious oligomerization of the amyloidogenic proteins. FEBS J 277(14):2940–2953. https://doi.org/10.1111/j.1742-4658.2010.07721.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Uversky VN, Oldfield CJ, Dunker AK (2008) Intrinsically disordered proteins in human diseases: introducing the D2 concept. Annu Rev Biophys 37:215–246. https://doi.org/10.1146/annurev.biophys.37.032807.125924

    Article  CAS  PubMed  Google Scholar 

  139. Uversky VN, Dave V, Iakoucheva LM, Malaney P, Metallo SJ, Pathak RR, Joerger AC (2014) Pathological unfoldomics of uncontrolled chaos: intrinsically disordered proteins and human diseases. Chem Rev 114(13):6844–6879. https://doi.org/10.1021/cr400713r

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Uversky VN (2014) Wrecked regulation of intrinsically disordered proteins in diseases: pathogenicity of deregulated regulators. Front Mol Biosci 1:6. https://doi.org/10.3389/fmolb.2014.00006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Dunker AK, Obradovic Z, Romero P, Garner EC, Brown CJ (2000) Intrinsic protein disorder in complete genomes. Genome Inform Ser Workshop Genome Inf 11:161–171

    CAS  Google Scholar 

  142. Ward JJ, Sodhi JS, McGuffin LJ, Buxton BF, Jones DT (2004) Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J Mol Biol 337(3):635–645

    Article  CAS  PubMed  Google Scholar 

  143. Xue B, Dunker AK, Uversky VN (2012) Orderly order in protein intrinsic disorder distribution: disorder in 3500 proteomes from viruses and the three domains of life. J Biomol Struct Dyn 30(2):137–149. https://doi.org/10.1080/07391102.2012.675145

    Article  CAS  PubMed  Google Scholar 

  144. Peng Z, Yan J, Fan X, Mizianty MJ, Xue B, Wang K, Hu G, Uversky VN, Kurgan L (2015) Exceptionally abundant exceptions: comprehensive characterization of intrinsic disorder in all domains of life. Cell Mol Life Sci 72(1):137–151. https://doi.org/10.1007/s00018-014-1661-9

    Article  CAS  PubMed  Google Scholar 

  145. Yan J, Cheng J, Kurgan L, Uversky VN (2020) Structural and functional analysis of “non-smelly” proteins. Cell Mol Life Sci 77(12):2423–2440. https://doi.org/10.1007/s00018-019-03292-1

    Article  CAS  PubMed  Google Scholar 

  146. DeForte S, Uversky VN (2016) Resolving the ambiguity: Making sense of intrinsic disorder when PDB structures disagree. Protein Sci 25(3):676–688. https://doi.org/10.1002/pro.2864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Le Gall T, Romero PR, Cortese MS, Uversky VN, Dunker AK (2007) Intrinsic disorder in the Protein Data Bank. J Biomol Struct Dyn 24(4):325–342. https://doi.org/10.1080/07391102.2007.10507123

    Article  PubMed  Google Scholar 

  148. Uversky VN (2013) Unusual biophysics of intrinsically disordered proteins. Biochim Biophys Acta 1834(5):932–951. https://doi.org/10.1016/j.bbapap.2012.12.008

    Article  CAS  PubMed  Google Scholar 

  149. Uversky VN (2013) Intrinsic disorder-based protein interactions and their modulators. Curr Pharm Des 19(23):4191–4213

    Article  CAS  PubMed  Google Scholar 

  150. Uversky VN (2015) Functional roles of transiently and intrinsically disordered regions within proteins. FEBS J 282(7):1182–1189. https://doi.org/10.1111/febs.13202

    Article  CAS  PubMed  Google Scholar 

  151. Uversky VN (2016) p53 proteoforms and intrinsic disorder: an illustration of the protein structure-function continuum concept. Int J Mol Sci 17(11):1874. https://doi.org/10.3390/ijms17111874

    Article  CAS  PubMed Central  Google Scholar 

  152. Habchi J, Tompa P, Longhi S, Uversky VN (2014) Introducing protein intrinsic disorder. Chem Rev 114(13):6561–6588. https://doi.org/10.1021/cr400514h

    Article  CAS  PubMed  Google Scholar 

  153. Iakoucheva LM, Radivojac P, Brown CJ, O’Connor TR, Sikes JG, Obradovic Z, Dunker AK (2004) The importance of intrinsic disorder for protein phosphorylation. Nucleic Acids Res 32(3):1037–1049. https://doi.org/10.1093/nar/gkh253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Pejaver V, Hsu WL, **n F, Dunker AK, Uversky VN, Radivojac P (2014) The structural and functional signatures of proteins that undergo multiple events of post-translational modification. Protein Sci 23(8):1077–1093. https://doi.org/10.1002/pro.2494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Uversky VN (2017) Intrinsically disordered proteins in overcrowded milieu: membrane-less organelles, phase separation, and intrinsic disorder. Curr Opin Struct Biol 44:18–30. https://doi.org/10.1016/j.sbi.2016.10.015

    Article  CAS  PubMed  Google Scholar 

  156. Uversky VN (2017) Protein intrinsic disorder-based liquid-liquid phase transitions in biological systems: complex coacervates and membrane-less organelles. Adv Colloid Interface Sci 239:97–114. https://doi.org/10.1016/j.cis.2016.05.012

    Article  CAS  PubMed  Google Scholar 

  157. Uversky VN (2021) Recent developments in the field of intrinsically disordered proteins: intrinsic disorder-based emergence in cellular biology in light of the physiological and pathological liquid-liquid phase transitions. Annu Rev Biophys 50(1):135–156. https://doi.org/10.1146/annurev-biophys-062920-063704

    Article  CAS  PubMed  Google Scholar 

  158. Dolgin E (2018) What lava lamps and vinaigrette can teach us about cell biology. Nature 555(7696):300–302. https://doi.org/10.1038/d41586-018-03070-2

    Article  CAS  PubMed  Google Scholar 

  159. Handwerger KE, Cordero JA, Gall JG (2005) Cajal bodies, nucleoli, and speckles in the Xenopus oocyte nucleus have a low-density, sponge-like structure. Mol Biol Cell 16(1):202–211. https://doi.org/10.1091/mbc.e04-08-0742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Strasser MJ, Mackenzie NC, Dumstrei K, Nakkrasae LI, Stebler J, Raz E (2008) Control over the morphology and segregation of Zebrafish germ cell granules during embryonic development. BMC Dev Biol 8:58. https://doi.org/10.1186/1471-213X-8-58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Brangwynne CP, Mitchison TJ, Hyman AA (2011) Active liquid-like behavior of nucleoli determines their size and shape in Xenopus laevis oocytes. Proc Natl Acad Sci U S A 108(11):4334–4339. https://doi.org/10.1073/pnas.1017150108

    Article  PubMed  PubMed Central  Google Scholar 

  162. Mitrea DM, Kriwacki RW (2016) Phase separation in biology; functional organization of a higher order. Cell Commun Signal 14:1. https://doi.org/10.1186/s12964-015-0125-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Banani SF, Lee HO, Hyman AA, Rosen MK (2017) Biomolecular condensates: organizers of cellular biochemistry. Nat Rev Mol Cell Biol 18(5):285–298. https://doi.org/10.1038/nrm.2017.7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Li P, Banjade S, Cheng HC, Kim S, Chen B, Guo L, Llaguno M, Hollingsworth JV, King DS, Banani SF, Russo PS, Jiang QX, Nixon BT, Rosen MK (2012) Phase transitions in the assembly of multivalent signalling proteins. Nature 483(7389):336–340. https://doi.org/10.1038/nature10879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Albertsson PA (1986) Partition of cell particles and macromolecules, 3rd edn. Wiley, New York

    Google Scholar 

  166. Zaslavsky BY (1994) Aqueous two-phase partitioning: physical chemistry and bioanalytical applications. Marcel Dekker, New York

    Google Scholar 

  167. Brangwynne CP (2013) Phase transitions and size scaling of membrane-less organelles. J Cell Biol 203(6):875–881. https://doi.org/10.1083/jcb.201308087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Brangwynne CP, Tompa P, Pappu RV (2015) Polymer physics of intracellular phase transitions. Nat Phys 11:899–904. https://doi.org/10.1038/nphys3532

    Article  CAS  Google Scholar 

  169. Uversky VN, Kuznetsova IM, Turoverov KK, Zaslavsky B (2015) Intrinsically disordered proteins as crucial constituents of cellular aqueous two phase systems and coacervates. FEBS Lett 589(1):15–22. https://doi.org/10.1016/j.febslet.2014.11.028

    Article  CAS  PubMed  Google Scholar 

  170. Dundr M, Misteli T (2010) Biogenesis of nuclear bodies. Cold Spring Harb Perspect Biol 2(12):a000711. https://doi.org/10.1101/cshperspect.a000711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Zhu L, Brangwynne CP (2015) Nuclear bodies: the emerging biophysics of nucleoplasmic phases. Curr Opin Cell Biol 34:23–30. https://doi.org/10.1016/j.ceb.2015.04.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Feric M, Vaidya N, Harmon TS, Mitrea DM, Zhu L, Richardson TM, Kriwacki RW, Pappu RV, Brangwynne CP (2016) Coexisting liquid phases underlie nucleolar subcompartments. Cell 165(7):1686–1697. https://doi.org/10.1016/j.cell.2016.04.047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Decker M, Jaensch S, Pozniakovsky A, Zinke A, O’Connell KF, Zachariae W, Myers E, Hyman AA (2011) Limiting amounts of centrosome material set centrosome size in C. elegans embryos. Curr Biol 21(15):1259–1267. https://doi.org/10.1016/j.cub.2011.06.002

    Article  CAS  PubMed  Google Scholar 

  174. Chuma S, Hosokawa M, Tanaka T, Nakatsuji N (2009) Ultrastructural characterization of spermatogenesis and its evolutionary conservation in the germline: germinal granules in mammals. Mol Cell Endocrinol 306(1–2):17–23. https://doi.org/10.1016/j.mce.2008.11.009

    Article  CAS  PubMed  Google Scholar 

  175. Kiebler MA, Bassell GJ (2006) Neuronal RNA granules: movers and makers. Neuron 51(6):685–690. https://doi.org/10.1016/j.neuron.2006.08.021

    Article  CAS  PubMed  Google Scholar 

  176. Decker CJ, Teixeira D, Parker R (2007) Edc3p and a glutamine/asparagine-rich domain of Lsm4p function in processing body assembly in Saccharomyces cerevisiae. J Cell Biol 179(3):437–449. https://doi.org/10.1083/jcb.200704147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Wippich F, Bodenmiller B, Trajkovska MG, Wanka S, Aebersold R, Pelkmans L (2013) Dual specificity kinase DYRK3 couples stress granule condensation/dissolution to mTORC1 signaling. Cell 152(4):791–805. https://doi.org/10.1016/j.cell.2013.01.033

    Article  CAS  PubMed  Google Scholar 

  178. Uniacke J, Zerges W (2008) Stress induces the assembly of RNA granules in the chloroplast of Chlamydomonas reinhardtii. J Cell Biol 182(4):641–646. https://doi.org/10.1083/jcb.200805125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Antonicka H, Shoubridge EA (2015) Mitochondrial RNA granules are centers for posttranscriptional RNA processing and ribosome biogenesis. Cell Rep. https://doi.org/10.1016/j.celrep.2015.01.030

    Article  PubMed  Google Scholar 

  180. Strzelecka M, Trowitzsch S, Weber G, Luhrmann R, Oates AC, Neugebauer KM (2010) Coilin-dependent snRNP assembly is essential for zebrafish embryogenesis. Nat Struct Mol Biol 17(4):403–409. https://doi.org/10.1038/nsmb.1783

    Article  CAS  PubMed  Google Scholar 

  181. Li B, Carey M, Workman JL (2007) The role of chromatin during transcription. Cell 128(4):707–719. https://doi.org/10.1016/j.cell.2007.01.015

    Article  CAS  PubMed  Google Scholar 

  182. Li L, Roy K, Katyal S, Sun X, Bleoo S, Godbout R (2006) Dynamic nature of cleavage bodies and their spatial relationship to DDX1 bodies, Cajal bodies, and gems. Mol Biol Cell 17(3):1126–1140. https://doi.org/10.1091/mbc.E05-08-0768

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Nizami Z, Deryusheva S, Gall JG (2010) The Cajal body and histone locus body. Cold Spring Harb Perspect Biol 2(7):a000653. https://doi.org/10.1101/cshperspect.a000653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Matera AG, Frey MR (1998) Coiled bodies and gems: Janus or gemini? Am J Hum Genet 63(2):317–321. https://doi.org/10.1086/301992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Gubitz AK, Feng W, Dreyfuss G (2004) The SMN complex. Exp Cell Res 296(1):51–56. https://doi.org/10.1016/j.yexcr.2004.03.022

    Article  CAS  PubMed  Google Scholar 

  186. Lamond AI, Spector DL (2003) Nuclear speckles: a model for nuclear organelles. Nat Rev Mol Cell Biol 4(8):605–612. https://doi.org/10.1038/nrm1172

    Article  CAS  PubMed  Google Scholar 

  187. Grossman E, Medalia O, Zwerger M (2012) Functional architecture of the nuclear pore complex. Annu Rev Biophys 41:557–584. https://doi.org/10.1146/annurev-biophys-050511-102328

    Article  CAS  PubMed  Google Scholar 

  188. Biamonti G, Vourc’h C (2010) Nuclear stress bodies. Cold Spring Harb Perspect Biol 2(6):a000695. https://doi.org/10.1101/cshperspect.a000695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Biamonti G (2004) Nuclear stress bodies: a heterochromatin affair? Nat Rev Mol Cell Biol 5(6):493–498. https://doi.org/10.1038/nrm1405

    Article  CAS  PubMed  Google Scholar 

  190. Shav-Tal Y, Blechman J, Darzacq X, Montagna C, Dye BT, Patton JG, Singer RH, Zipori D (2005) Dynamic sorting of nuclear components into distinct nucleolar caps during transcriptional inhibition. Mol Biol Cell 16(5):2395–2413. https://doi.org/10.1091/mbc.E04-11-0992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Harrigan JA, Belotserkovskaya R, Coates J, Dimitrova DS, Polo SE, Bradshaw CR, Fraser P, Jackson SP (2011) Replication stress induces 53BP1-containing OPT domains in G1 cells. J Cell Biol 193(1):97–108. https://doi.org/10.1083/jcb.201011083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Huang S (2000) Review: perinucleolar structures. J Struct Biol 129(2–3):233–240. https://doi.org/10.1006/jsbi.2000.4247

    Article  CAS  PubMed  Google Scholar 

  193. Fox AH, Lam YW, Leung AK, Lyon CE, Andersen J, Mann M, Lamond AI (2002) Paraspeckles: a novel nuclear domain. Curr Biol 12(1):13–25

    Article  CAS  PubMed  Google Scholar 

  194. Maul GG, Negorev D, Bell P, Ishov AM (2000) Review: properties and assembly mechanisms of ND10, PML bodies, or PODs. J Struct Biol 129(2–3):278–287. https://doi.org/10.1006/jsbi.2000.4239

    Article  CAS  PubMed  Google Scholar 

  195. Pirrotta V, Li HB (2012) A view of nuclear Polycomb bodies. Curr Opin Genet Dev 22(2):101–109. https://doi.org/10.1016/j.gde.2011.11.004

    Article  CAS  PubMed  Google Scholar 

  196. Boeynaems S, Alberti S, Fawzi NL, Mittag T, Polymenidou M, Rousseau F, Schymkowitz J, Shorter J, Wolozin B, Van Den Bosch L, Tompa P, Fuxreiter M (2018) Protein phase separation: a new phase in cell biology. Trends Cell Biol 28(6):420–435. https://doi.org/10.1016/j.tcb.2018.02.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Turoverov KK, Kuznetsova IM, Fonin AV, Darling AL, Zaslavsky BY, Uversky VN (2019) Stochasticity of biological soft matter: emerging concepts in intrinsically disordered proteins and biological phase separation. Trends Biochem Sci 44(8):716–728. https://doi.org/10.1016/j.tibs.2019.03.005

    Article  CAS  PubMed  Google Scholar 

  198. Darling AL, Liu Y, Oldfield CJ, Uversky VN (2018) Intrinsically disordered proteome of human membrane-less organelles. Proteomics 18(5–6):e1700193. https://doi.org/10.1002/pmic.201700193

    Article  CAS  PubMed  Google Scholar 

  199. Zhou HX, Nguemaha V, Mazarakos K, Qin S (2018) Why do disordered and structured proteins behave differently in phase separation? Trends Biochem Sci 43(7):499–516. https://doi.org/10.1016/j.tibs.2018.03.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Fonin AV, Silonov SA, Shpironok OG, Antifeeva IA, Petukhov AV, Romanovich AE, Kuznetsova IM, Uversky VN, Turoverov KK (2021) The Role of non-specific interactions in canonical and ALT-associated PML-bodies formation and dynamics. Int J Mol Sci. https://doi.org/10.3390/ijms22115821

    Article  PubMed  PubMed Central  Google Scholar 

  201. Williamson DJ, Owen DM, Rossy J, Magenau A, Wehrmann M, Gooding JJ, Gaus K (2011) Pre-existing clusters of the adaptor Lat do not participate in early T cell signaling events. Nat Immunol 12(7):655–662. https://doi.org/10.1038/ni.2049

    Article  CAS  PubMed  Google Scholar 

  202. Maszewski J, Kwiatkowska M (1984) Number, size, and transcriptional activity of nucleoli during different periods of interphase in antheridial filaments of Chara vulgaris L. Folia Histochem Cytobiol 22(1):9–19

    CAS  PubMed  Google Scholar 

  203. Anderson P, Kedersha N (2009) Stress granules. Curr Biol 19(10):R397–R398. https://doi.org/10.1016/J.CUB.2009.03.013

    Article  CAS  PubMed  Google Scholar 

  204. Lyon AS, Peeples WB, Rosen MK (2021) A framework for understanding the functions of biomolecular condensates across scales. Nat Rev Mol Cell Biol. https://doi.org/10.1038/s41580-020-00303-z

    Article  PubMed  Google Scholar 

  205. Weber APSC (2019) Evidence for and against Liquid-Liquid Phase Separation in the Nucleus. Non-coding RNA. https://doi.org/10.3390/ncrna5040050

    Article  PubMed  PubMed Central  Google Scholar 

  206. Boke E, Ruer M, Wühr M, Coughlin M, Lemaitre R, Gygi SP, Alberti S, Drechsel D, Hyman AA, Mitchison TJ (2016) Amyloid-like self-assembly of a cellular compartment. Cell 166(3):637–650. https://doi.org/10.1016/J.CELL.2016.06.051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Alberti S, Gladfelter A, Mittag T (2019) Considerations and Challenges in Studying Liquid-Liquid Phase Separation and Biomolecular Condensates. Cell 176(3):419–434. https://doi.org/10.1016/j.cell.2018.12.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. King MR, Petry S (2020) Phase separation of TPX2 enhances and spatially coordinates microtubule nucleation. Nat Commun 11(1):1–13. https://doi.org/10.1038/s41467-019-14087-0

    Article  CAS  Google Scholar 

  209. Peeples W, Rosen MK (2020) Phase separation can increase enzyme activity by concentration and molecular organization. bioRxiv. https://doi.org/10.1101/2020.09.15.299115

    Article  Google Scholar 

  210. Powers SK, Holehouse AS, Korasick DA, Schreiber KH, Clark NM, **g H, Emenecker R, Han S, Tycksen E, Hwang I, Sozzani R, Jez JM, Pappu RV, Strader LC (2019) Nucleo-cytoplasmic partitioning of ARF proteins controls auxin responses in Arabidopsis thaliana. Mol Cell 76(1):177-190.e175. https://doi.org/10.1016/J.MOLCEL.2019.06.044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Su X, Ditlev JA, Hui E, **ng W, Banjade S, Okrut J, King DS, Taunton J, Rosen MK, Vale RD (2016) Phase separation of signaling molecules promotes T cell receptor signal transduction. Science 352(6285):595–599. https://doi.org/10.1126/science.aad9964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Case LB, Zhang X, Ditlev JA, Rosen MK (2019) Stoichiometry controls activity of phase-separated clusters of actin signaling proteins. Science (New York, NY) 363(6431):1093–1097. https://doi.org/10.1126/SCIENCE.AAU6313

    Article  CAS  Google Scholar 

  213. Frottin F, Schueder F, Tiwary S, Gupta R, Körner R, Schlichthaerle T, Cox J, Jungmann R, Hartl FU, Hipp MS (2019) The nucleolus functions as a phase-separated protein quality control compartment. Science (New York, NY) 365(6451):342–347. https://doi.org/10.1126/SCIENCE.AAW9157

    Article  CAS  Google Scholar 

  214. Deviri D, Safran SA (2021) Physical theory of biological noise buffering by multicomponent phase separation. Proc Natl Acad Sci USA 118:25. https://doi.org/10.1073/PNAS.2100099118/SUPPL_FILE/PNAS.2100099118.SAPP.PDF

    Article  Google Scholar 

  215. Riback JA, Katanski CD, Kear-Scott JL, Pilipenko EV, Rojek AE, Sosnick TR, Drummond DA (2017) Stress-triggered phase separation is an adaptive evolutionarily tuned response. Cell 168(6):1028-1040.e1019. https://doi.org/10.1016/J.CELL.2017.02.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Bergeron-Sandoval L-P, Heris HK, Chang C, Cornell CE, Keller SL, François P, Hendricks AG, Ehrlicher AJ, Pappu RV, Michnick SW (2018) Endocytosis caused by liquid-liquid phase separation of proteins. bioRxiv. https://doi.org/10.1101/145664

    Article  Google Scholar 

  217. Molliex A, Temirov J, Lee J, Coughlin M, Kanagaraj AP, Kim HJ, Mittag T, Taylor JP (2015) Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 163(1):123–133. https://doi.org/10.1016/j.cell.2015.09.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Jiang H, Wang S, Huang Y, He X, Cui H, Zhu X, Zheng Y (2015) Phase transition of spindle-associated protein regulate spindle apparatus assembly. Cell 163(1):108–122. https://doi.org/10.1016/j.cell.2015.08.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Nott TJ, Petsalaki E, Farber P, Jervis D, Fussner E, Plochowietz A, Craggs TD, Bazett-Jones DP, Pawson T, Forman-Kay JD, Baldwin AJ (2015) Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. Mol Cell 57(5):936–947. https://doi.org/10.1016/j.molcel.2015.01.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Andersen JS, Lam YW, Leung AKL, Ong SE, Lyon CE, Lamond AI, Mann M (2005) Nucleolar proteome dynamics. Nature 433(7021):77–83. https://doi.org/10.1038/NATURE03207

    Article  CAS  PubMed  Google Scholar 

  221. Kim W, Kim DY, Lee KH (2021) RNA-binding proteins and the complex pathophysiology of ALS. Int J Mol Sci. https://doi.org/10.3390/ijms22052598

    Article  PubMed  PubMed Central  Google Scholar 

  222. Darling AL, Shorter J (2021) Combating deleterious phase transitions in neurodegenerative disease. Biochim Biophys Acta Mol Cell Res 1868(5):118984. https://doi.org/10.1016/j.bbamcr.2021.118984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Webber CJ, Lei SE, Wolozin B (2020) The pathophysiology of neurodegenerative disease: disturbing the balance between phase separation and irreversible aggregation. Prog Mol Biol Transl Sci 174:187–223. https://doi.org/10.1016/bs.pmbts.2020.04.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Babinchak WM, Surewicz WK (2020) Liquid-liquid phase separation and its mechanistic role in pathological protein aggregation. J Mol Biol 432(7):1910–1925. https://doi.org/10.1016/j.jmb.2020.03.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Verdile V, De Paola E, Paronetto MP (2019) Aberrant phase transitions: side effects and novel therapeutic strategies in human disease. Front Genet 10:173. https://doi.org/10.3389/fgene.2019.00173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Hofweber M, Dormann D (2019) Friend or foe-Post-translational modifications as regulators of phase separation and RNP granule dynamics. J Biol Chem 294(18):7137–7150. https://doi.org/10.1074/jbc.TM118.001189

    Article  CAS  PubMed  Google Scholar 

  227. Patel A, Lee HO, Jawerth L, Maharana S, Jahnel M, Hein MY, Stoynov S, Mahamid J, Saha S, Franzmann TM (2015) A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162(5):1066–1077

    Article  CAS  PubMed  Google Scholar 

  228. Carey JL, Guo L (2022) Liquid-liquid phase separation of TDP-43 and FUS in physiology and pathology of neurodegenerative diseases. Front Mol Biosci. https://doi.org/10.3389/FMOLB.2022.826719

    Article  PubMed  PubMed Central  Google Scholar 

  229. Boyko S, Surewicz WK (2022) Tau liquid-liquid phase separation in neurodegenerative diseases. Trends Cell Biol. https://doi.org/10.1016/J.TCB.2022.01.011

    Article  PubMed  Google Scholar 

  230. Darling AL, Dahrendorff J, Creodore SG, Dickey CA, Blair LJ, Uversky VN (2021) Small heat shock protein 22 kDa can modulate the aggregation and liquid-liquid phase separation behavior of tau. Protein Sci 30(7):1350–1359. https://doi.org/10.1002/pro.4060

    Article  CAS  PubMed  Google Scholar 

  231. Ray S, Singh N, Kumar R, Patel K, Pandey S, Datta D, Mahato J, Panigrahi R, Navalkar A, Mehra S, Gadhe L, Chatterjee D, Sawner AS, Maiti S, Bhatia S, Gerez JA, Chowdhury A, Kumar A, Padinhateeri R, Riek R, Krishnamoorthy G, Maji SK (2020) α-Synuclein aggregation nucleates through liquid-liquid phase separation. Nat Chem 12(8):705–716. https://doi.org/10.1038/s41557-020-0465-9

    Article  CAS  PubMed  Google Scholar 

  232. Boeynaems S, Tompa P, Van Den Bosch L (2018) Phasing in on the cell cycle. Cell Div 13:1. https://doi.org/10.1186/s13008-018-0034-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Mahboubi H (1863) Stochaj U (2017) Cytoplasmic stress granules: Dynamic modulators of cell signaling and disease. Biochim Biophys Acta 4:884–895. https://doi.org/10.1016/j.bbadis.2016.12.022

    Article  CAS  Google Scholar 

  234. Kuechler ER, Budzyńska PM, Bernardini JP, Gsponer J, Mayor T (2020) Distinct features of stress granule proteins predict localization in membraneless organelles. J Mol Biol 432(7):2349–2368. https://doi.org/10.1016/j.jmb.2020.02.020

    Article  CAS  PubMed  Google Scholar 

  235. Khong A, Matheny T, Jain S, Mitchell SF, Wheeler JR, Parker R (2017) The stress granule transcriptome reveals principles of mRNA accumulation in stress granules. Mol Cell 68(4):808-820e805. https://doi.org/10.1016/j.molcel.2017.10.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Yang P, Mathieu C, Kolaitis RM, Zhang P, Messing J, Yurtsever U, Yang Z, Wu J, Li Y, Pan Q, Yu J, Martin EW, Mittag T, Kim HJ, Taylor JP (2020) G3BP1 Is a tunable switch that triggers phase separation to assemble stress granules. Cell 181(2):325-345e328. https://doi.org/10.1016/j.cell.2020.03.046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Protter DSW, Parker R (2016) Principles and properties of stress granules. Trends Cell Biol 26(9):668–679. https://doi.org/10.1016/j.tcb.2016.05.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Jain S, Wheeler JR, Walters RW, Agrawal A, Barsic A, Parker R (2016) ATPase-modulated stress granules contain a diverse proteome and substructure. Cell 164(3):487–498. https://doi.org/10.1016/j.cell.2015.12.038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Guillen-Boixet J, Kopach A, Holehouse AS, Wittmann S, Jahnel M, Schlussler R, Kim K, Trussina I, Wang J, Mateju D, Poser I, Maharana S, Ruer-Gruss M, Richter D, Zhang X, Chang YT, Guck J, Honigmann A, Mahamid J, Hyman AA, Pappu RV, Alberti S, Franzmann TM (2020) RNA-induced conformational switching and clustering of G3BP drive stress granule assembly by condensation. Cell 181(2):346-361 e317. https://doi.org/10.1016/j.cell.2020.03.049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Cao X, ** X, Liu B (2020) The involvement of stress granules in aging and aging-associated diseases. Aging Cell 19(4):e13136. https://doi.org/10.1111/acel.13136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Elbaum-Garfinkle S (2019) Matter over mind: Liquid phase separation and neurodegeneration. J Biol Chem 294(18):7160–7168. https://doi.org/10.1074/jbc.REV118.001188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Tüű-Szabó B, Hoffka G, Duro N (1867) Fuxreiter M (2019) Altered dynamics may drift pathological fibrillization in membraneless organelles. Biochim Biophys Acta 10:988–998. https://doi.org/10.1016/j.bbapap.2019.04.005

    Article  CAS  Google Scholar 

  243. Marijan D, Tse R, Elliott K, Chandhok S, Luo M, Lacroix E, Audas TE (2019) Stress-specific aggregation of proteins in the amyloid bodies. FEBS Lett 593(22):3162–3172. https://doi.org/10.1002/1873-3468.13597

    Article  CAS  PubMed  Google Scholar 

  244. Marmor-Kollet H, Siany A, Kedersha N, Knafo N, Rivkin N, Danino YM, Moens TG, Olender T, Sheban D, Cohen N, Dadosh T, Addadi Y, Ravid R, Eitan C, Toth Cohen B, Hofmann S, Riggs CL, Advani VM, Higginbottom A, Cooper-Knock J, Hanna JH, Merbl Y, Van Den Bosch L, Anderson P, Ivanov P, Geiger T, Hornstein E (2020) Spatiotemporal proteomic analysis of stress granule disassembly using APEX reveals regulation by SUMOylation and links to ALS pathogenesis. Mol Cell 80(5):876-891e876. https://doi.org/10.1016/j.molcel.2020.10.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Moujaber O, Mahboubi H, Kodiha M, Bouttier M, Bednarz K, Bakshi R, White J, Larose L, Colmegna I, Stochaj U (2017) Dissecting the molecular mechanisms that impair stress granule formation in aging cells. Biochim Biophys Acta Mol Cell Res 1864(3):475–486. https://doi.org/10.1016/j.bbamcr.2016.12.008

    Article  CAS  PubMed  Google Scholar 

  246. Shiina N (2019) Liquid- and solid-like RNA granules form through specific scaffold proteins and combine into biphasic granules. J Biol Chem 294(10):3532–3548. https://doi.org/10.1074/jbc.RA118.005423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Shin Y, Brangwynne CP (2017) Liquid phase condensation in cell physiology and disease. Science. https://doi.org/10.1126/science.aaf4382

    Article  PubMed  PubMed Central  Google Scholar 

  248. Wang Z, Zhang H (2019) Phase separation, transition, and autophagic degradation of proteins in development and pathogenesis. Trends Cell Biol 29(5):417–427. https://doi.org/10.1016/j.tcb.2019.01.008

    Article  CAS  PubMed  Google Scholar 

  249. Wang M, Tao X, Jacob MD, Bennett CA, Ho JJD, Gonzalgo ML, Audas TE, Lee S (2018) Stress-induced low complexity RNA activates physiological amyloidogenesis. Cell Rep 24(7):1713-1721.e1714. https://doi.org/10.1016/J.CELREP.2018.07.040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Audas TE, Audas DE, Jacob MD, Ho JJD, Khacho M, Wang M, Perera JK, Gardiner C, Bennett CA, Head T, Kryvenko ON, Jorda M, Daunert S, Malhotra A, Trinkle-Mulcahy L, Gonzalgo ML, Lee S (2016) Adaptation to stressors by systemic protein amyloidogenesis. Dev Cell 39(2):155–168. https://doi.org/10.1016/J.DEVCEL.2016.09.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Wegmann S, Eftekharzadeh B, Tepper K, Zoltowska KM, Bennett RE, Dujardin S, Laskowski PR, MacKenzie D, Kamath T, Commins C, Vanderburg C, Roe AD, Fan Z, Molliex AM, Hernandez-Vega A, Muller D, Hyman AA, Mandelkow E, Taylor JP, Hyman BT (2018) Tau protein liquid–liquid phase separation can initiate tau aggregation. EMBO J 37(7):e98049–e98049. https://doi.org/10.15252/EMBJ.201798049

    Article  PubMed  PubMed Central  Google Scholar 

  252. Gaglia G, Rashid R, Yapp C, Joshi GN, Li CG, Lindquist SL, Sarosiek KA, Whitesell L, Sorger PK, Santagata S (2020) HSF1 phase transition mediates stress adaptation and cell fate decisions. Nat Cell Biol 22(2):151–158. https://doi.org/10.1038/s41556-019-0458-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Watanabe K, Ohtsuki T (2021) Inhibition of HSF1 and SAFB granule formation enhances apoptosis induced by heat stress. Int J Mol Sci 22(9):4982–4982. https://doi.org/10.3390/IJMS22094982

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Ninomiya K, Adachi S, Natsume T, Iwakiri J, Terai G, Asai K, Hirose T (2020) LncRNA-dependent nuclear stress bodies promote intron retention through SR protein phosphorylation. EMBO J 39(3):e102729–e102729. https://doi.org/10.15252/EMBJ.2019102729

    Article  CAS  PubMed  Google Scholar 

  255. Jarmuz M, Glotzbach CD, Bailey KA, Bandyopadhyay R, Shaffer LG (2007) The Evolution of satellite III DNA subfamilies among primates. Am J Hum Genet 80(3):495–501. https://doi.org/10.1086/512132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Jolly C, Lakhotia SC (2006) Human sat III and Drosophila hsrω transcripts: a common paradigm for regulation of nuclear RNA processing in stressed cells. Nucleic Acids Res 34(19):5508–5514. https://doi.org/10.1093/NAR/GKL711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Prasanth KV, Rajendra TK, Lal AK, Lakhotia SC (2000) Omega speckles - a novel class of nuclear speckles containing hnRNPs associated with noncoding hsr-omega RNA in Drosophila. J Cell Sci 13 Pt 19(19):3485–3497. https://doi.org/10.1242/JCS.113.19.3485

    Article  Google Scholar 

  258. Riviere M, Bernhard W (1960) Examen au microscope électronique de la tumeur VX2 du lapin domestique dérivée du papillome de Shope. Bull Cancer 47:570–584

    Google Scholar 

  259. Bernardi R, Pandolfi PP (2007) Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nat Rev Mol Cell Biol 8(12):1006–1016. https://doi.org/10.1038/nrm2277

    Article  CAS  PubMed  Google Scholar 

  260. Corpet A, Kleijwegt C, Roubille S, Juillard F, Jacquet K, Texier P, Lomonte P (2020) PML nuclear bodies and chromatin dynamics: catch me if you can! Nucleic Acids Res 48(21):11890–11912. https://doi.org/10.1093/nar/gkaa828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Weidtkamp-Peters S, Lenser T, Negorev D, Gerstner N, Hofmann TG, Schwanitz G, Hoischen C, Maul G, Dittrich P, Hemmerich P (2008) Dynamics of component exchange at PML nuclear bodies. J Cell Sci 121(Pt 16):2731–2743. https://doi.org/10.1242/jcs.031922

    Article  CAS  PubMed  Google Scholar 

  262. Nisole S, Maroui MA, Mascle XH, Aubry M, Chelbi-Alix MK (2013) Differential roles of PML isoforms. Front Oncol 3:125. https://doi.org/10.3389/fonc.2013.00125

    Article  PubMed  PubMed Central  Google Scholar 

  263. Li Y, Ma X, Chen Z, Wu H, Wang P, Wu W, Cheng N, Zeng L, Zhang H, Cai X, Chen SJ, Chen Z, Meng G (2019) B1 oligomerization regulates PML nuclear body biogenesis and leukemogenesis. Nat Commun 10(1):3789. https://doi.org/10.1038/s41467-019-11746-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Wang P, Benhenda S, Wu H, Lallemand-Breitenbach V, Zhen T, Jollivet F, Peres L, Li Y, Chen SJ, Chen Z, de Thé H, Meng G (2018) RING tetramerization is required for nuclear body biogenesis and PML sumoylation. Nat Commun 9(1):1277. https://doi.org/10.1038/s41467-018-03498-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Li C, Peng Q, Wan X, Sun H, Tang J (2017) C-terminal motifs in promyelocytic leukemia protein isoforms critically regulate PML nuclear body formation. J Cell Sci 130(20):3496–3506. https://doi.org/10.1242/jcs.202879

    Article  CAS  PubMed  Google Scholar 

  266. Rajpal G, Arvan P (2013) Chapter 236—disulfide bond formation. In: Kastin AJ (ed) Handbook of biologically active peptides, 2nd edn. Academic Press, Boston, pp 1721–1729. https://doi.org/10.1016/B978-0-12-385095-9.00236-0

    Chapter  Google Scholar 

  267. Fonin AV, Silonov SA, Fefilova AS, Stepanenko OV, Gavrilova AA, Petukhov AV, Romanovich AE, Modina AL, Zueva TS, Nedelyaev EM, Pleskach NM, Kuranova ML, Kuznetsova IM, Uversky VN, Turoverov KK (2022) New evidence of the importance of weak interactions in the formation of PML-bodies. Int J Mol Sci. https://doi.org/10.3390/ijms23031613

    Article  PubMed  PubMed Central  Google Scholar 

  268. Le Ferrand H, Duchamp M, Gabryelczyk B, Cai H, Miserez A (2019) Time-resolved observations of liquid-liquid phase separation at the nanoscale using in situ liquid transmission electron microscopy. J Am Chem Soc 141(17):7202–7210. https://doi.org/10.1021/jacs.9b03083

    Article  CAS  PubMed  Google Scholar 

  269. Alshareedah I, Kaur T, Banerjee PR (2021) Methods for characterizing the material properties of biomolecular condensates. In: Methods in enzymology, vol 646. https://doi.org/10.1016/bs.mie.2020.06.009

  270. Wang J, Choi JM, Holehouse AS, Lee HO, Zhang X, Jahnel M, Maharana S, Lemaitre R, Pozniakovsky A, Drechsel D, Poser I, Pappu RV, Alberti S, Hyman AA (2018) A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins. Cell. https://doi.org/10.1016/j.cell.2018.06.006

    Article  PubMed  PubMed Central  Google Scholar 

  271. Gui X, Luo F, Li Y, Zhou H, Qin Z, Liu Z, Gu J, **e M, Zhao K, Dai B, Shin WS, He J, He L, Jiang L, Zhao M, Sun B, Li X, Liu C, Li D (2019) Structural basis for reversible amyloids of hnRNPA1 elucidates their role in stress granule assembly. Nat Commun. https://doi.org/10.1038/s41467-019-09902-7

    Article  PubMed  PubMed Central  Google Scholar 

  272. Alshareedah I, Kaur T, Ngo J, Seppala H, Kounatse LAD, Wang W, Moosa MM, Banerjee PR (2019) Interplay between short-range attraction and long-range repulsion controls reentrant liquid condensation of ribonucleoprotein-RNA complexes. J Am Chem Soc. https://doi.org/10.1021/jacs.9b03689

    Article  PubMed  PubMed Central  Google Scholar 

  273. Elbaum-Garfinkle S, Kim Y, Szczepaniak K, Chen CC, Eckmann CR, Myong S, Brangwynne CP (2015) The disordered P granule protein LAF-1 drives phase separation into droplets with tunable viscosity and dynamics. Proc Natl Acad Sci U S A 112(23):7189–7194. https://doi.org/10.1073/pnas.1504822112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Hansen AS, Woringer M, Grimm JB, Lavis LD, Tjian R, Darzacq X (2018) Robust model-based analysis of single-particle tracking experiments with spot-on. Elife. https://doi.org/10.7554/eLife.33125

    Article  PubMed  PubMed Central  Google Scholar 

  275. Shen H, Tauzin LJ, Baiyasi R, Wang W, Moringo N, Shuang B, Landes CF (2017) Single particle tracking: from theory to biophysical applications. Chem Rev. https://doi.org/10.1021/acs.chemrev.6b00815

    Article  PubMed  Google Scholar 

  276. Babinchak WM, Haider R, Dumm BK, Sarkar P, Surewicz K, Choi JK, Surewicz WK (2019) The role of liquid-liquid phase separation in aggregation of the TDP-43 low-complexity domain. J Biol Chem. https://doi.org/10.1074/jbc.RA118.007222

    Article  PubMed  PubMed Central  Google Scholar 

  277. Jawerth LM, Ijavi M, Ruer M, Saha S, Jahnel M, Hyman AA, Jülicher F, Fischer-Friedrich E (2018) Salt-dependent rheology and surface tension of protein condensates using optical traps. Phys Rev Lett. https://doi.org/10.1103/PhysRevLett.121.258101

    Article  PubMed  Google Scholar 

  278. Zhou HX (2020) Determination of condensate material properties from droplet deformation. J Phys Chem B. https://doi.org/10.1021/acs.jpcb.0c06230

    Article  PubMed  PubMed Central  Google Scholar 

  279. Zhou HX (2021) Viscoelasticity of biomolecular condensates conforms to the Jeffreys model. J Chem Phys. https://doi.org/10.1063/5.0038916

    Article  PubMed  PubMed Central  Google Scholar 

  280. Taylor NO, Wei MT, Stone HA, Brangwynne CP (2019) Quantifying dynamics in phase-separated condensates using fluorescence recovery after photobleaching. Biophys J. https://doi.org/10.1016/j.bpj.2019.08.030

    Article  PubMed  PubMed Central  Google Scholar 

  281. Mitrea DM, Chandra B, Ferrolino MC, Gibbs EB, Tolbert M, White MR, Kriwacki RW (2018) Methods for physical characterization of phase-separated bodies and membrane-less organelles. J Mol Biol 430(23):4773–4805. https://doi.org/10.1016/j.jmb.2018.07.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Wei MT, Elbaum-Garfinkle S, Holehouse AS, Chen CCH, Feric M, Arnold CB, Priestley RD, Pappu RV, Brangwynne CP (2017) Phase behaviour of disordered proteins underlying low density and high permeability of liquid organelles. Nat Chem. https://doi.org/10.1038/NCHEM.2803

    Article  PubMed  Google Scholar 

  283. Spector DL, Lamond AI (2011) Nuclear speckles. Cold Spring Harb Perspect Biol 3(2):a000646–a000646. https://doi.org/10.1101/cshperspect.a000646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. Brady JP, Farber PJ, Sekhar A, Lin YH, Huang R, Bah A, Nott TJ, Chan HS, Baldwin AJ, Forman-Kay JD, Kay LE (2017) Structural and hydrodynamic properties of an intrinsically disordered region of a germ cell-specific protein on phase separation. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.1706197114

    Article  PubMed  PubMed Central  Google Scholar 

  285. Strom AR, Emelyanov AV, Mir M, Fyodorov DV, Darzacq X, Karpen GH (2017) Phase separation drives heterochromatin domain formation. Nature. https://doi.org/10.1038/nature22989

    Article  PubMed  PubMed Central  Google Scholar 

  286. Ulbrich R (2017) Beyond the limit: the world of super-resolution microscopy. Am Lab 49(8)

  287. Raška I (2003) Oldies but goldies: searching for Christmas trees within the nucleolar architecture. Trends Cell Biol. https://doi.org/10.1016/j.tcb.2003.08.003

    Article  PubMed  Google Scholar 

  288. Swift H (1959) Studies on nuclear fine structure. Brookhaven Symp Biol. https://doi.org/10.1016/0014-4827(65)90200-4

    Article  PubMed  Google Scholar 

  289. Gall JG, Bellini M, Za W, Murphy C (1999) Assembly of the nuclear transcription and processing machinery: Cajal bodies (coiled bodies) and transcriptosomes. Mol Biol Cell 10:12. https://doi.org/10.1091/mbc.10.12.4385

    Article  Google Scholar 

  290. Franzmann TM, Jahnel M, Pozniakovsky A, Mahamid J, Holehouse AS, Nüske E, Richter D, Baumeister W, Grill SW, Pappu RV, Hyman AA, Alberti S (2018) Phase separation of a yeast prion protein promotes cellular fitness. Science. https://doi.org/10.1126/science.aao5654

    Article  PubMed  PubMed Central  Google Scholar 

  291. Patel A, Lee HO, Jawerth L, Maharana S, Jahnel M, Hein MY, Stoynov S, Mahamid J, Saha S, Franzmann TM, Pozniakovski A, Poser I, Maghelli N, Royer LA, Weigert M, Myers EW, Grill S, Drechsel D, Hyman AA, Alberti S (2015) A Liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162(5):1066–1077. https://doi.org/10.1016/j.cell.2015.07.047

    Article  CAS  PubMed  Google Scholar 

  292. Schaffer M, Pfeffer S, Mahamid J, Kleindiek S, Laugks T, Albert S, Engel BD, Rummel A, Smith AJ, Baumeister W, Plitzko JM (2019) A cryo-FIB lift-out technique enables molecular-resolution cryo-ET within native Caenorhabditis elegans tissue. Nat Methods 16(8):757–762. https://doi.org/10.1038/s41592-019-0497-5

    Article  CAS  PubMed  Google Scholar 

  293. Conicella AE, Zerze GH, Mittal J, Fawzi NL (2016) ALS mutations disrupt phase separation mediated by α-helical structure in the TDP-43 low-complexity C-terminal domain. Structure. https://doi.org/10.1016/j.str.2016.07.007

    Article  PubMed  PubMed Central  Google Scholar 

  294. Stender EGP, Ray S, Norrild RK, Larsen JA, Petersen D, Farzadfard A, Galvagnion C, Jensen H, Buell AK, Norrild RK (2021) Capillary flow experiments for thermodynamic and kinetic characterization of protein liquid-liquid phase separation. Nat Commun. https://doi.org/10.1038/s41467-021-27433-y

    Article  PubMed  PubMed Central  Google Scholar 

  295. Otzen DE, Buell AK, Jensen H (2021) Microfluidics and the quantification of biomolecular interactions. Curr Opin Struct Biol. https://doi.org/10.1016/j.sbi.2021.02.006

    Article  PubMed  Google Scholar 

  296. Bremer A, Mittag T, Heymann M (2020) Microfluidic characterization of macromolecular liquid-liquid phase separation. bioRxiv. https://doi.org/10.1101/2020.06.16.154518

    Article  Google Scholar 

  297. Linsenmeier M, Kopp MRG, Stavrakis S, de Mello A, Arosio P (2021) Analysis of biomolecular condensates and protein phase separation with microfluidic technology. Biochim Biophys Acta Mol Cell Res. https://doi.org/10.1016/j.bbamcr.2020.118823

    Article  PubMed  Google Scholar 

  298. Taylor N, Elbaum-Garfinkle S, Vaidya N, Zhang H, Stone HA, Brangwynne CP (2016) Biophysical characterization of organelle-based RNA/protein liquid phases using microfluidics. Soft Matter. https://doi.org/10.1039/C6SM01087C

    Article  PubMed  PubMed Central  Google Scholar 

  299. Dormann D (2020) FG-nucleoporins caught in the act of liquid-liquid phase separation. J Cell Biol. https://doi.org/10.1083/jcb.201910211

    Article  PubMed  PubMed Central  Google Scholar 

  300. Rho HS, Gardeniers H (2020) Microfluidic Droplet-Storage Array. Micromachines 11(6):608–608. https://doi.org/10.3390/MI11060608

    Article  PubMed Central  Google Scholar 

  301. Van Lindt J, Bratek-Skicki A, Nguyen PN, Pakravan D, Durán-Armenta LF, Tantos A, Pancsa R, Van Den Bosch L, Maes D, Tompa P (2021) A generic approach to study the kinetics of liquid–liquid phase separation under near-native conditions. Commun Biol 4(1):77–77. https://doi.org/10.1038/s42003-020-01596-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  302. Shin Y, Berry J, Pannucci N, Haataja MP, Toettcher JE, Brangwynne CP (2017) Spatiotemporal control of intracellular phase transitions using light-activated optodroplets. Cell 168(1–2):159-171e114. https://doi.org/10.1016/j.cell.2016.11.054

    Article  CAS  PubMed  Google Scholar 

  303. Bracha D, Walls MT, Wei MT, Zhu L, Kurian M, Avalos JL, Toettcher JE, Brangwynne CP (2018) Map** local and global liquid phase behavior in living cells using photo-oligomerizable seeds. Cell 175(6):1467-1480e1413. https://doi.org/10.1016/j.cell.2018.10.048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  304. Dine E, Gil AA, Uribe G, Brangwynne CP, Toettcher JE (2018) Protein phase separation provides long-term memory of transient spatial stimuli. Cell Syst 6(6):655-663 e655. https://doi.org/10.1016/j.cels.2018.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  305. Zhu L, Richardson TM, Wacheul L, Wei MT, Feric M, Whitney G, Lafontaine DLJ, Brangwynne CP (2019) Controlling the material properties and rRNA processing function of the nucleolus using light. Proc Natl Acad Sci U S A 116(35):17330–17335. https://doi.org/10.1073/pnas.1903870116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  306. Fonin AV, Antifeeva IA, Shpironok OG, Stepanenko OV, Silonov SA, Stepanenko OV, Antifeev IE, Romanovich AE, Kuznetsova IM, Kim J-I, Uversky VN, Turoverov KK (2021) Photo-dependent membrane-less organelles formed from plant phyB and PIF6 proteins in mammalian cells. Int J Biol Macromol 176:325–331. https://doi.org/10.1016/j.ijbiomac.2021.02.075

    Article  CAS  PubMed  Google Scholar 

  307. Sanders DW, Kedersha N, Lee DSW, Strom AR, Drake V, Riback JA, Bracha D, Eeftens JM, Iwanicki A, Wang A, Wei MT, Whitney G, Lyons SM, Anderson P, Jacobs WM, Ivanov P, Brangwynne CP (2020) Competing protein-RNA interaction networks control multiphase intracellular organization. Cell 181(2):306-324 e328. https://doi.org/10.1016/j.cell.2020.03.050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  308. Liu ZS, Cai H, Xue W, Wang M, **a T, Li WJ, **ng JQ, Zhao M, Huang YJ, Chen S, Wu SM, Wang X, Liu X, Pang X, Zhang ZY, Li T, Dai J, Dong F, **a Q, Li AL, Zhou T, Liu ZG, Zhang XM, Li T (2019) G3BP1 promotes DNA binding and activation of cGAS. Nat Immunol 20(1):18–28. https://doi.org/10.1038/s41590-018-0262-4

    Article  CAS  PubMed  Google Scholar 

  309. Shin Y, Chang YC, Lee DSW, Berry J, Sanders DW, Ronceray P, Wingreen NS, Haataja M, Brangwynne CP (2018) Liquid nuclear condensates mechanically sense and restructure the genome. Cell 175(6):1481-1491e1413. https://doi.org/10.1016/j.cell.2018.10.057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  310. Aguilera-Gomez A, Rabouille C (2017) Membrane-bound organelles versus membrane-less compartments and their control of anabolic pathways in Drosophila. Dev Biol 428(2):310–317. https://doi.org/10.1016/j.ydbio.2017.03.029

    Article  CAS  PubMed  Google Scholar 

  311. Dimova R, Lipowsky R (2012) Lipid membranes in contact with aqueous phases of polymer solutions. Soft Matter 8(24):6409–6415. https://doi.org/10.1039/C2SM25261A

    Article  CAS  Google Scholar 

  312. Nesterov SV, Ilyinsky NS (1868) Uversky VN (2021) Liquid-liquid phase separation as a common organizing principle of intracellular space and biomembranes providing dynamic adaptive responses. Biochim Biophys Acta Mol Cell Res 11:119102. https://doi.org/10.1016/j.bbamcr.2021.119102

    Article  CAS  Google Scholar 

  313. Yamasaki A, Alam JM, Noshiro D, Hirata E, Fujioka Y, Suzuki K, Ohsumi Y, Noda NN (2020) Liquidity is a critical determinant for selective autophagy of protein condensates. Mol Cell 77(6):1163-1175e1169. https://doi.org/10.1016/j.molcel.2019.12.026

    Article  CAS  PubMed  Google Scholar 

  314. Zhang G, Wang Z, Du Z, Zhang H (2018) mTOR regulates phase separation of PGL granules to modulate their autophagic degradation. Cell 174(6):1492-1506e1422. https://doi.org/10.1016/j.cell.2018.08.006

    Article  CAS  PubMed  Google Scholar 

  315. Beutel O, Maraspini R, Pombo-Garcia K, Martin-Lemaitre C, Honigmann A (2019) Phase separation of zonula occludens proteins drives formation of tight junctions. Cell 179(4):923-936e911. https://doi.org/10.1016/j.cell.2019.10.011

    Article  CAS  PubMed  Google Scholar 

  316. Ma W, Mayr C (2018) A membraneless organelle associated with the endoplasmic reticulum enables 3’UTR-mediated protein-protein interactions. Cell 175(6):1492-1506e1419. https://doi.org/10.1016/j.cell.2018.10.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  317. Zacharogianni M, Aguilera-Gomez A, Veenendaal T, Smout J, Rabouille C (2014) A stress assembly that confers cell viability by preserving ERES components during amino-acid starvation. Elife. https://doi.org/10.7554/eLife.04132

    Article  PubMed  PubMed Central  Google Scholar 

  318. Zhao YG, Zhang H (2020) Phase Separation in Membrane Biology: The Interplay between Membrane-Bound Organelles and Membraneless Condensates. Dev Cell 55(1):30–44. https://doi.org/10.1016/j.devcel.2020.06.033

    Article  CAS  PubMed  Google Scholar 

  319. Lafontaine DLJ, Riback JA, Bascetin R, Brangwynne CP (2021) The nucleolus as a multiphase liquid condensate. Nat Rev Mol Cell Biol 22(3):165–182. https://doi.org/10.1038/s41580-020-0272-6

    Article  CAS  PubMed  Google Scholar 

  320. Yoneda M, Nakagawa T, Hattori N, Ito T (2021) The nucleolus from a liquid droplet perspective. J Biochem 170(2):153–162. https://doi.org/10.1093/jb/mvab090

    Article  CAS  PubMed  Google Scholar 

  321. y Cajal SR (1910) El núcleo de las células piramidales del cerebro humano y de algunos mamíferos

  322. Machyna M, Heyn P, Neugebauer KM (2013) Cajal bodies: where form meets function. WIREs RNA 4(1):17–34. https://doi.org/10.1002/wrna.1139

    Article  CAS  PubMed  Google Scholar 

  323. Lallemand-Breitenbach V, de Thé H (2018) PML nuclear bodies: from architecture to function. Curr Opin Cell Biol 52:154–161

    Article  CAS  PubMed  Google Scholar 

  324. Schul W, Van Der Kraan I, Matera AG, Van Driel R, De Jong L (1999) Nuclear domains enriched in RNA 3’-processing factors associate with coiled bodies and histone genes in a cell cycle-dependent manner. Mol Biol Cell 10(11):3815–3824. https://doi.org/10.1091/mbc.10.11.3815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  325. Callan HG, Lloyd L (1960) Lampbrush chromosomes of crested newts Triturus cristatus (Laurenti). Philos Trans R Soc Lond Ser B Biol Sci 243(702):135–219. https://doi.org/10.1098/RSTB.1960.0007

    Article  Google Scholar 

  326. Liu Q, Dreyfuss G (1996) A novel nuclear structure containing the survival of motor neurons protein. EMBO J. https://doi.org/10.1002/j.1460-2075.1996.tb00725.x

    Article  PubMed  PubMed Central  Google Scholar 

  327. Pombo A, Cuello P, Schul W, Yoon JB, Roeder RG, Cook PR, Murphy S (1998) Regional and temporal specialization in the nucleus: a transcriptionally-active nuclear domain rich in PTF, Oct1 and PIKA antigens associates with specific chromosomes early in the cell cycle. EMBO J 17(6):1768–1778. https://doi.org/10.1093/EMBOJ/17.6.1768

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  328. Kloc M, Bilinski S, Etkin LD (2004) The Balbiani body and germ cell determinants: 150 years later. Curr Top Dev Biol 59:1–36. https://doi.org/10.1016/S0070-2153(04)59001-4

    Article  CAS  PubMed  Google Scholar 

  329. Kloc M, Jedrzejowska I, Tworzydlo W, Bilinski SM (2014) Balbiani body, nuage and sponge bodies–term plasm pathway players. Arthropod Struct Dev 43(4):341–348. https://doi.org/10.1016/J.ASD.2013.12.003

    Article  PubMed  Google Scholar 

  330. Fox AH, Nakagawa S, Hirose T, Bond CS (2018) Paraspeckles: where long noncoding RNA meets phase separation. Trends Biochem Sci 43(2):124–135. https://doi.org/10.1016/j.tibs.2017.12.001

    Article  CAS  PubMed  Google Scholar 

  331. Saurin AJ, Shiels C, Williamson J, Satijn DPE, Otte AP, Sheer D, Freemont PS (1998) The human polycomb group complex associates with pericentromeric heterochromatin to form a novel nuclear domain. J Cell Biol 142(4):887–898. https://doi.org/10.1083/JCB.142.4.887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  332. Chen T, Boisvert FM, Bazett-Jones DP, Richard S (1999) A role for the GSG domain in localizing Sam68 to novel nuclear structures in cancer cell lines. Mol Biol Cell 10(9):3015–3015. https://doi.org/10.1091/MBC.10.9.3015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  333. Rajan P, Dalgliesh C, Bourgeois CF, Heiner M, Emami K, Clark EL, Bindereif A, Stevenin J, Robson CN, Leung HY, Elliott DJ (2009) Proteomic identification of heterogeneous nuclear ribonucleoprotein L as a novel component of SLM/Sam68 nuclear bodies. BMC Cell Biol 10(1):1–13. https://doi.org/10.1186/1471-2121-10-82/FIGURES/6

    Article  Google Scholar 

  334. Mannen T, Yamashita S, Tomita K, Goshima N, Hirose T (2016) The Sam68 nuclear body is composed of two RNase-sensitive substructures joined by the adaptor HNRNPL. J Cell Biol 214(1):45–59. https://doi.org/10.1083/JCB.201601024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  335. Bashkirov VI, Scherthan H, Solinger JA, Buerstedde J-M, Heyer W-D (1997) A mouse cytoplasmic exoribonuclease (mXRN1p) with preference for G4 tetraplex substrates. J Cell Biol 136(4):761–773. https://doi.org/10.1083/jcb.136.4.761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  336. Riggs CL, Kedersha N, Ivanov P, Anderson P (2020) Mammalian stress granules and P bodies at a glance. J Cell Sci. https://doi.org/10.1242/jcs.242487

    Article  PubMed  Google Scholar 

  337. Kedersha NL, Gupta M, Li W, Miller I, Anderson P (1999) RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2 alpha to the assembly of mammalian stress granules. J Cell Biol 147(7):1431–1442. https://doi.org/10.1083/jcb.147.7.1431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported in part by a grant from Russian Science Foundation (RSCF 19-15-00107 (KKT)) and an RF President Fellowship (SP-259.2019.4 (IAA)).

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  1. Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, Tikhoretsky Av., 4, St. Petersburg, 194064, Russia

    Iuliia A. Antifeeva, Alexander V. Fonin, Anna S. Fefilova, Olesya V. Stepanenko, Olga I. Povarova, Sergey A. Silonov, Irina M. Kuznetsova & Konstantin K. Turoverov

  2. Department of Molecular Medicine and USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd. MDC07, Tampa, FL, 33612, USA

    Vladimir N. Uversky

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  1. Iuliia A. Antifeeva
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  2. Alexander V. Fonin
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  4. Olesya V. Stepanenko
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Contributions

AVF, IMG, VNU, and KKT: study conception and design, collection of literature data, data curation, formal analysis, evaluation, interpretation of data, writing and review of the manuscript, and study supervision. IAA: collection of literature, data, data curation, formal analysis, evaluation, acquisition and interpretation of data, writing and review of the manuscript, visualization; ASF, OVS, OIP, SAS: collection of literature, data, data curation, formal analysis, evaluation, acquisition and interpretation of data, writing and review of the manuscript.

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Correspondence to Vladimir N. Uversky or Konstantin K. Turoverov.

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Antifeeva, I.A., Fonin, A.V., Fefilova, A.S. et al. Liquid–liquid phase separation as an organizing principle of intracellular space: overview of the evolution of the cell compartmentalization concept. Cell. Mol. Life Sci. 79, 251 (2022). https://doi.org/10.1007/s00018-022-04276-4

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