1932

Abstract

Biological phase separation is known to be important for cellular organization, which has recently been extended to a new class of biomolecules that form liquid-like droplets coexisting with the surrounding cellular or extracellular environment. These droplets are termed membraneless organelles, as they lack a dividing lipid membrane, and are formed through liquid-liquid phase separation (LLPS). Elucidating the molecular determinants of phase separation is a critical challenge for the field, as we are still at the early stages of understanding how cells may promote and regulate functions that are driven by LLPS. In this review, we discuss the role that disorder, perturbations to molecular interactions resulting from sequence, posttranslational modifications, and various regulatory stimuli play on protein LLPS, with a particular focus on insights that may be obtained from simulation and theory. We finally discuss how these molecular driving forces alter multicomponent phase separation and selectivity.

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2020-04-20
2024-03-29
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Literature Cited

  1. 1. 
    Shin Y, Brangwynne CP 2017. Liquid phase condensation in cell physiology and disease. Science 3576357eaaf4382
  2. 2. 
    Brangwynne CP, Eckmann CR, Courson DS, Rybarska A, Hoege C 2009. Germline P granules are liquid droplets that localize by controlled dissolution/condensation. Science 32459351729–32
  3. 3. 
    Li P, Banjade S, Cheng H-C, Kim S, Chen B 2012. Phase transitions in the assembly of multi-valent signaling proteins. Nature 4837389336–40
  4. 4. 
    Riback JA, Katanski CD, Kear-Scott JL, Pilipenko EV, Rojek AE 2017. Stress-triggered phase separation is an adaptive, evolutionarily tuned response. Cell 16861028–40
  5. 5. 
    Wei M-T, Elbaum-Garfinkle S, Holehouse AS, Chen CC-H, Feric M 2017. Phase behaviour of disordered proteins underlying low density and high permeability of liquid organelles. Nat. Chem. 9111118–25
  6. 6. 
    Schuster BS, Reed EH, Parthasarathy R, Jahnke CN, Caldwell RM 2018. Controllable protein phase separation and modular recruitment to form responsive membraneless organelles. Nat. Commun. 912985
  7. 7. 
    Patel A, Lee HO, Jawerth L, Maharana S, Jahnel M 2015. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 16251066–77
  8. 8. 
    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 2491537–49
  9. 9. 
    Wegmann S, Eftekharzadeh B, Tepper K, Zoltowska KM, Bennett RE 2018. Tau protein liquid–liquid phase separation can initiate tau aggregation. EMBO J. 377e98049
  10. 10. 
    Darling AL, Liu Y, Oldfield CJ, Uversky VN 2018. Intrinsically disordered proteome of human membrane-less organelles. Proteomics 185–61700193
  11. 11. 
    Van Der Lee R, Buljan M, Lang B, Weatheritt RJ, Daughdrill GW 2014. Classification of intrinsically disordered regions and proteins. Chem. Rev. 114136589–631
  12. 12. 
    Uversky VN, Gillespie JR, Fink AL 2000. Why are “natively unfolded” proteins unstructured under physiologic conditions. Proteins 41415–27
  13. 13. 
    Muiznieks LD, Sharpe S, Pomès R, Keeley FW 2018. Role of liquid-liquid phase separation in assembly of elastin and other extracellular matrix proteins. J. Mol. Biol. 430234741–53
  14. 14. 
    Kim HJ, Kim NC, Wang Y-D, Scarborough EA, Moore J 2013. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 4957442467–73
  15. 15. 
    Mittag T, Parker R 2018. Multiple modes of protein-protein interactions promote RNP granule assembly. J. Mol. Biol. 430234636–49
  16. 16. 
    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. 589115–22
  17. 17. 
    García Quiroz F, Chilkoti A 2015. Sequence heuristics to encode phase behaviour in intrinsically disordered protein polymers. Nat. Mater. 14111164–71
  18. 18. 
    Dignon GL, Zheng W, Kim YC, Best RB, Mittal J 2018. Sequence determinants of protein phase behavior from a coarse-grained model. PLOS Comput. Biol. 141e1005941
  19. 19. 
    Brady JP, Farber PJ, Sekhar A, Lin Y-H, Huang R 2017. Structural and hydrodynamic properties of an intrinsically disordered region of a germ cell-specific protein on phase separation. PNAS 11439E8194–203
  20. 20. 
    Burke KA, Janke AM, Rhine CL, Fawzi NL 2015. Residue-by-residue view of in vitro FUS granules that bind the C-terminal domain of RNA polymerase II. Mol. Cell 602231–41
  21. 21. 
    Murthy AC, Dignon GL, Kan Y, Zerze GH, Parekh SH 2019. Molecular interactions underlying liquid-liquid phase separation of the FUS low-complexity domain. Nat. Struct. Mol. Biol. 26637–48
  22. 22. 
    Galea CA, Wang Y, Sivakolundu SG, Kriwacki RW 2008. Regulation of cell division by intrinsically unstructured proteins: intrinsic flexibility, modularity, and signaling conduits. Biochemistry 47297598–609
  23. 23. 
    Wang JT, Smith J, Chen B-C, Schmidt H, Rasoloson D 2014. Regulation of RNA granule dynamics by phosphorylation of serine-rich, intrinsically disordered proteins in C. elegans. eLife 3e04591
  24. 24. 
    Monahan Z, Ryan VH, Janke AM, Burke KA, Zerze GH 2017. Phosphorylation of FUS low-complexity domain disrupts phase separation, aggregation, and toxicity. EMBO J. 36202951–67
  25. 25. 
    Larson AG, Elnatan D, Keenen MM, Trnka MJ, Johnston JB 2017. Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature 5477662236–40
  26. 26. 
    Ryan VH, Dignon GL, Zerze GH, Chabata CV, Silva R 2018. Mechanistic view of hnRNPA2 low-complexity domain structure, interactions, and phase separation altered by mutation and arginine methylation. Mol. Cell 393465–79
  27. 27. 
    Saito M, Hess D, Eglinger J, Fritsch AW, Kreysing M 2019. Acetylation of intrinsically disordered regions regulates phase separation. Nat. Chem. Biol. 15151–61
  28. 28. 
    Lin Y-H, Chan HS 2017. Phase separation and single-chain compactness of charged disordered proteins are strongly correlated. Biophys. J. 112102043–46
  29. 29. 
    Dignon GL, Zheng W, Best RB, Kim YC, Mittal J 2018. Relation between single-molecule properties and phase behavior of intrinsically disordered proteins. PNAS 115409929–34
  30. 30. 
    Hofmann H, Soranno A, Borgia A, Gast K, Nettels D, Schuler B 2012. Polymer scaling laws of unfolded and intrinsically disordered proteins quantified with single-molecule spectroscopy. PNAS 10916155–60
  31. 31. 
    Riback JA, Bowman MA, Zmyslowski AM, Knoverek CR, Jumper JM 2017. Innovative scattering analysis shows that hydrophobic proteins are expanded in water. Science 358238–41
  32. 32. 
    Zheng W, Zerze GH, Borgia A, Mittal J, Schuler B, Best RB 2018. Inferring properties of disordered chains from FRET transfer efficiencies. J. Chem. Phys. 14812123329
  33. 33. 
    Marsh JA, Forman-Kay JD 2010. Sequence determinants of compaction in intrinsically disordered proteins. Biophys. J. 98102383–90
  34. 34. 
    Flory PJ 1949. The configuration of real polymer chains. J. Chem. Phys. 17303–10
  35. 35. 
    Mao AH, Crick SL, Vitalis A, Chicoine C, Pappu RV 2010. Net charge per residue modulates conformational ensembles of intrinsically disordered proteins. PNAS 1078183–88
  36. 36. 
    Borgia A, Borgia MB, Bugge K, Kissling VM, Heidarsson PO 2018. Extreme disorder in an ultrahigh-affinity protein complex. Nature 555769461–66
  37. 37. 
    Fuertes G, Banterle N, Ruff KM, Chowdhury A, Mercadante D 2017. Decoupling of size and shape fluctuations in heteropolymeric sequences reconciles discrepancies in SAXS versus FRET measurements. PNAS 114E6342–51
  38. 38. 
    Zheng W, Best RB 2018. An extended Guinier analysis for intrinsically disordered proteins. J. Mol. Biol. 4302540–53
  39. 39. 
    Panagiotopoulos AZ, Wong V, Floriano MA 1998. Phase equilibria of lattice polymers from histogram reweighting Monte Carlo simulations. Macromolecules 313912–18
  40. 40. 
    Rauscher S, Pomès R 2017. The liquid structure of elastin. eLife 6e26526
  41. 41. 
    Dignon GL, Zheng W, Mittal J 2019. Simulation methods for liquid–liquid phase separation of disordered proteins. Curr. Opin. Chem. Eng. 2392–98
  42. 42. 
    Zhao B, Li NK, Yingling YG, Hall CK 2015. LCST behavior is manifested in a single molecule: elastin-like polypeptide (VPGVG)n. Biomacromolecules 171111–18
  43. 43. 
    Dignon GL, Zheng W, Kim YC, Mittal J 2019. Temperature-controlled liquid–liquid phase separation of disordered proteins. ACS Cent. Sci. 55821–30
  44. 44. 
    Kroschwald S, Munder MC, Maharana S, Franzmann TM, Richter D 2018. Different material states of Pub1 condensates define distinct modes of stress adaptation and recovery. Cell Rep. 23113327–39
  45. 45. 
    Wang A, Conicella AE, Schmidt HB, Martin EW, Rhoads SN 2018. A single N-terminal phosphomimic disrupts TDP-43 polymerization, phase separation, and RNA splicing. EMBO J. 375e97452
  46. 46. 
    Mitrea DM, Cika JA, Stanley CB, Nourse A, Onuchic PL 2018. Self-interaction of NPM1 modulates multiple mechanisms of liquid–liquid phase separation. Nat. Commun. 91842
  47. 47. 
    An S, Kumar R, Sheets ED, Benkovic SJ 2008. Reversible compartmentalization of de novo purine biosynthetic complexes in living cells. Science 3205872103–6
  48. 48. 
    Sabari BR, Dall'Agnese A, Boija A, Klein IA, Coffey EL 2018. Coactivator condensation at super-enhancers links phase separation and gene control. Science 3616400eaar3958
  49. 49. 
    Asherie N 2004. Protein crystallization and phase diagrams. Methods 343266–72
  50. 50. 
    Braun MK, Wolf M, Matsarskaia O, Da Vela S, Roosen-Runge F 2017. Strong isotope effects on effective interactions and phase behavior in protein solutions in the presence of multivalent ions. J. Phys. Chem. B 12171731–39
  51. 51. 
    Jiang L-L, Che M-X, Zhao J, Zhou C-J, Xie M-Y 2013. Structural transformation of the amyloidogenic core region of TDP-43 protein initiates its aggregation and cytoplasmic inclusion. J. Biol. Chem. 2882719614–24
  52. 52. 
    Shin Y, Berry J, Pannucci N, Haataja MP, Toettcher JE, Brangwynne CP 2017. Spatiotemporal control of intracellular phase transitions using light-activated optodroplets. Cell 1681159–71
  53. 53. 
    Bracha D, Walls MT, Wei M-T, Zhu L, Kurian M 2018. Mapping local and global liquid phase behavior in living cells using photo-oligomerizable seeds. Cell 17561467–80
  54. 54. 
    Loughlin FE, Lukavsky PJ, Kazeeva T, Reber S, Hock E-M 2019. The solution structure of FUS bound to RNA reveals a bipartite mode of RNA recognition with both sequence and shape specificity. Mol. Cell 733490–504
  55. 55. 
    Knott M, Best RB 2014. Discriminating binding mechanisms of an intrinsically disordered protein via a multistate coarse-grained model. J. Chem. Phys. 14017175102
  56. 56. 
    Bah A, Vernon RM, Siddiqui Z, Krzeminski M, Muhandiram R 2015. Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch. Nature 5197541106–9
  57. 57. 
    Conicella AE, Dignon GL, Zerze GH, Schmidt HB, Alexandra M 2019. TDP-43 α-helical structure tunes liquid-liquid phase separation and function. bioRxiv 640615. https://doi.org/10.1101/640615
    [Crossref]
  58. 58. 
    Roberts S, Harmon TS, Schaal J, Miao V, Li KJ 2018. Injectable tissue integrating networks from recombinant polypeptides with tunable order. Nat. Mater. 17121154–63
  59. 59. 
    Prouteau M, Loewith R 2018. Regulation of cellular metabolism through phase separation of enzymes. Biomolecules 84E160
  60. 60. 
    Jankowsky E 2011. RNA helicases at work: binding and rearranging. Trends Biochem. Sci. 36119–29
  61. 61. 
    Rai AK, Chen J-X, Selbach M, Pelkmans L 2018. Kinase-controlled phase transition of membraneless organelles in mitosis. Nature 5597713211–16
  62. 62. 
    Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN 2005. Flexible nets: the roles of intrinsic disorder in protein interaction networks. FEBS J. 272205129–48
  63. 63. 
    Markmiller S, Soltanieh S, Server KL, Mak R, Jin W 2018. Context-dependent and disease-specific diversity in protein interactions within stress granules. Cell 1723590–604
  64. 64. 
    Chakraborty AK 2001. Disordered heteropolymers: models for biomimetic polymers and polymers with frustrating quenched disorder. Phys. Rep. 34211–61
  65. 65. 
    Amaya J, Ryan VH, Fawzi NL 2018. The SH3 domain of Fyn kinase interacts with and induces liquid–liquid phase separation of the low-complexity domain of hnRNPA2. J. Biol. Chem. 2935119522–31
  66. 66. 
    Zhang H, Elbaum-Garfinkle S, Langdon EM, Taylor N, Occhipinti P 2015. RNA controls polyQ protein phase transitions. Mol. Cell 602220–30
  67. 67. 
    Langdon EM, Qiu Y, Niaki AG, McLaughlin GA, Weidmann CA 2018. mRNA structure determines specificity of a polyQ-driven phase separation. Science 3606391922–27
  68. 68. 
    Khoury GA, Baliban RC, Floudas CA 2011. Proteome-wide post-translational modification statistics: frequency analysis and curation of the Swiss-Prot database. Sci. Rep. 190
  69. 69. 
    Gomes E, Shorter J 2018. Molecular language of membraneless organelles. J. Biol. Chem. 294187115–27
  70. 70. 
    Bentley EP, Frey BB, Deniz AA 2019. Physical chemistry of cellular liquid-phase separation. Chem. Eur. J. 25225600–10
  71. 71. 
    Elbaum-Garfinkle S, Kim Y, Szczepaniak K, Chen CC-H, Eckmann CR 2015. The disordered P granule protein LAF-1 drives phase separation into droplets with tunable viscosity and dynamics. PNAS 112237189–94
  72. 72. 
    Nott TJ, Petsalaki E, Farber P, Jervis D, Fussner E 2015. Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. Mol. Cell 575936–47
  73. 73. 
    Nott TJ, Craggs TD, Baldwin AJ 2016. Membraneless organelles can melt nucleic acid duplexes and act as biomolecular filters. Nat. Chem. 86569–75
  74. 74. 
    Pak CW, Kosno M, Holehouse AS, Padrick SB, Mittal A 2016. Sequence determinants of intracellular phase separation by complex coacervation of a disordered protein. Mol. Cell 63172–85
  75. 75. 
    Lin Y, McCarty J, Rauch JN, Delaney KT, Kosik KS 2019. Narrow equilibrium window for complex coacervation of tau and RNA under cellular conditions. eLife 8e42571
  76. 76. 
    Lytle TK, Chang L-W, Markiewicz N, Perry SL, Sing CE 2019. Designing electrostatic interactions via polyelectrolyte monomer sequence. ACS Cent. Sci. 54709–18
  77. 77. 
    Samanta HS, Chakraborty D, Thirumalai D 2018. Charge fluctuation effects on the shape of flexible polyampholytes with applications to intrinsically disordered proteins. J. Chem. Phys. 14916163323
  78. 78. 
    Martin EW, Holehouse AS, Grace CR, Hughes A, Pappu RV, Mittag T 2016. Sequence determinants of the conformational properties of an intrinsically disordered protein prior to and upon multisite phosphorylation. J. Am. Chem. Soc. 1384715323–35
  79. 79. 
    Isom DG, Castañeda CA, Cannon BR, García-Moreno EB 2011. Large shifts in pKa values of lysine residues buried inside a protein. PNAS 108135260–65
  80. 80. 
    Lin Y, Currie SL, Rosen MK 2017. Intrinsically disordered sequences enable modulation of protein phase separation through distributed tyrosine motifs. J. Biol. Chem. 2924619110–20
  81. 81. 
    Li H-R, Chiang W-C, Chou P-C, Wang W-J, Huang J-R 2018. TAR DNA-binding protein 43 (TDP-43) liquid–liquid phase separation is mediated by just a few aromatic residues. JBC 293166090–98
  82. 82. 
    Martinez CR, Iverson BL 2012. Rethinking the term “pi-stacking. .” Chem. Sci. 372191–201
  83. 83. 
    Schottel BL, Chifotides HT, Dunbar KR 2008. Anion-π interactions. Chem. Soc. Rev. 37168–83
  84. 84. 
    Dougherty DA 2012. The cation-π interaction. Acc. Chem. Res. 464885–93
  85. 85. 
    Vernon RM, Chong PA, Tsang B, Kim TH, Bah A 2018. Pi-pi contacts are an overlooked protein feature relevant to phase separation. eLife 7e31486
  86. 86. 
    Gallivan JP, Dougherty DA 1999. Cation-π interactions in structural biology. PNAS 96179459–64
  87. 87. 
    Wang J, Choi J-M, Holehouse AS, Lee HO, Zhang X 2018. A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins. Cell 1743688–99
  88. 88. 
    Shakya A, King JT 2018. Non-Fickian molecular transport in protein–DNA droplets. ACS Macro Lett. 7101220–25
  89. 89. 
    Dill KA 1997. Theory for the folding and stability of globular proteins. Biochemistry 241501–9
  90. 90. 
    Fromm SA, Kamenz J, Nöldeke ER, Neu A, Zocher G, Sprangers R 2014. In vitro reconstitution of a cellular phase-transition process that involves the mRNA decapping machinery. Angew. Chem. Int. Ed. 53287354–59
  91. 91. 
    Mitrea DM, Cika JA, Guy CS, Ban D, Banerjee PR 2016. Nucleophosmin integrates within the nucleolus via multi-modal interactions with proteins displaying R-rich linear motifs and rRNA. eLife 5e13571
  92. 92. 
    Shih J-W, Wang W-T, Tsai T-Y, Kuo C-Y, Li H-K, Lee Y-HW 2012. Critical roles of RNA helicase DDX3 and its interactions with eIF4E/PABP1 in stress granule assembly and stress response. Biochem. J. 4411119–29
  93. 93. 
    Tarakanova A, Huang W, Weiss AS, Kaplan DL, Buehler MJ 2017. Computational smart polymer design based on elastin protein mutability. Biomaterials 12749–60
  94. 94. 
    Cheng AC, Chen WW, Fuhrmann CN, Frankel AD 2003. Recognition of nucleic acid bases and base-pairs by hydrogen bonding to amino acid side-chains. J. Mol. Biol. 3274781–96
  95. 95. 
    Zagrovic B, Bartonek L, Polyansky AA 2018. RNA-protein interactions in an unstructured context. FEBS Lett. 592172901–16
  96. 96. 
    Zaslavsky BY, Ferreira LA, Darling AL, Uversky VN 2018. The solvent side of proteinaceous membrane-less organelles in light of aqueous two-phase systems. Int. J. Biol. Macromol. 1171224–51
  97. 97. 
    Murray DT, Kato M, Lin Y, Thurber KR, Hung I 2017. Structure of FUS protein fibrils and its relevance to self-assembly and phase separation of low-complexity domains. Cell 1713615–27
  98. 98. 
    Hughes MP, Sawaya MR, Boyer DR, Goldschmidt L, Rodriguez JA 2018. Atomic structures of low-complexity protein segments reveal kinked β sheets that assemble networks. Science 3596376698–701
  99. 99. 
    Guenther EL, Cao Q, Trinh H, Lu J, Sawaya MR 2018. Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation. Nat. Struct. Mol. Biol. 256463–71
  100. 100. 
    Ackermann BE, Debelouchina GT 2019. Heterochromatin protein HP1α gelation dynamics revealed by solid-state NMR spectroscopy. Angew. Chem. 58196300–5
  101. 101. 
    Das RK, Pappu RV 2013. Conformations of intrinsically disordered proteins are influenced by linear sequence distributions of oppositely charged residues. PNAS 11013392–97
  102. 102. 
    Sawle L, Ghosh K 2015. A theoretical method to compute sequence dependent configurational properties in charged polymers and proteins. J. Chem. Phys. 1438085101
  103. 103. 
    Das S, Amin AN, Lin Y-H, Chan HS 2018. Coarse-grained residue-based models of disordered protein condensates: utility and limitations of simple charge pattern parameters. Phys. Chem. Chem. Phys. 204528558–74
  104. 104. 
    Khokhlov AR, Khalatur PG 1999. Conformation-dependent sequence design (engineering) of AB copolymers. Phys. Rev. Lett. 82173456
  105. 105. 
    Ashbaugh HS 2009. Tuning the globular assembly of hydrophobic/hydrophilic heteropolymer sequences. J. Phys. Chem. B 1134314043–46
  106. 106. 
    Brangwynne CP, Tompa P, Pappu RV 2015. Polymer physics of intracellular phase transitions. Nat. Phys. 1111899–904
  107. 107. 
    Cuylen S, Blaukopf C, Politi AZ, Müller-Reichert T, Neumann B 2016. Ki-67 acts as a biological surfactant to disperse mitotic chromosomes. Nature 5357611308–12
  108. 108. 
    Molliex A, Temirov J, Lee J, Coughlin M, Kanagaraj AP 2015. Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 1631123–33
  109. 109. 
    Lin Y-H, Brady JP, Forman-Kay JD, Chan HS 2017. Charge pattern matching as a fuzzymode of molecular recognition for the functional phase separations of intrinsically disordered proteins. New J. Phys. 1911115003
  110. 110. 
    Falahati H, Wieschaus E 2017. Independent active and thermodynamic processes govern the nucleolus assembly in vivo. PNAS 11461335–40
  111. 111. 
    Nakashima KK, Baaij JF, Spruijt E 2018. Reversible generation of coacervate droplets in an enzymatic network. Soft Matter 143361–67
  112. 112. 
    Balu R, Dutta NK, Choudhury NR, Elvin CM, Lyons RE 2014. An16-resilin: an advanced multi-stimuli-responsive resilin-mimetic protein polymer. Acta Biomater. 10114768–77
  113. 113. 
    Ruff KM, Roberts S, Chilkoti A, Pappu RV 2018. Advances in understanding stimulus responsive phase behavior of intrinsically disordered protein polymers. J. Mol. Biol. 430234619–35
  114. 114. 
    Zerze GH, Best RB, Mittal J 2015. Sequence- and temperature-dependent properties of unfolded and disordered proteins from atomistic simulations. J. Phys. Chem. B 1194614622–30
  115. 115. 
    Privalov PL, Makhatadze GI 1993. Contribution of hydration to protein folding thermodynamics. II. The entropy and Gibbs energy of hydration. J. Mol. Biol. 232660–79
  116. 116. 
    Garde S, García AE, Pratt LR, Hummer G 1999. Temperature dependence of the solubility of non-polar gases in water. Biophys. Chem. 781–221–32
  117. 117. 
    Huang DM, Chandler D 2000. Temperature and length scale dependence of hydrophobic effects and their possible implications for protein folding. PNAS 97158324–27
  118. 118. 
    Chandler D 2005. Interfaces and the driving force of hydrophobic assembly. Nature 437640–47
  119. 119. 
    Dill KA, Alonso DO, Hutchinson K 1989. Thermal stabilities of globular proteins. Biochemistry 28135439–49
  120. 120. 
    Van Dijk E, Varilly P, Knowles TP, Frenkel D, Abeln S 2016. Consistent treatment of hydrophobicity in protein lattice models accounts for cold denaturation. Phys. Rev. Lett. 1167078101
  121. 121. 
    Debye P, Hückel E 1923. De la théorie des électrolytes. I. Abaissement du point de congélation et phénomènes associés. Phys. Z. 249185–206
  122. 122. 
    Zhang Y, Cremer PS 2010. Chemistry of Hofmeister anions and osmolytes. Annu. Rev. Phys. Chem. 6163–83
  123. 123. 
    Onuchic PL, Milin AN, Alshareedah I, Deniz AA, Banerjee PR 2019. Divalent cations can control a switch-like behavior in heterotypic and homotypic RNA coacervates. Sci. Rep. 912161
  124. 124. 
    Brangwynne CP, Mitchison TJ, Hyman AA 2011. Active liquid-like behavior of nucleoli determines their size and shape in Xenopus laevis oocytes. PNAS 108114334–39
  125. 125. 
    Altmeyer M, Neelsen KJ, Teloni F, Pozdnyakova I, Pellegrino S 2015. Liquid demixing of intrinsically disordered proteins is seeded by poly(ADP-ribose). Nat. Commun. 68088
  126. 126. 
    Patel A, Malinovska L, Saha S, Wang J, Alberti S 2017. ATP as a biological hydrotrope. Science 3566339753–56
  127. 127. 
    Wurtz JD, Lee CF 2018. Stress granule formation via ATP depletion-triggered phase separation. New J. Phys. 204045008
  128. 128. 
    Putnam A, Cassani M, Smith J, Seydoux G 2019. A gel phase promotes condensation of liquid P granules in Caenorhabditis elegans embryos. Nat. Struct. Mol. Biol. 26220–26
  129. 129. 
    Choi K-J, Tsoi PS, Moosa MM, Paulucci-Holthauzen A, Liao S-CJ 2018. A chemical chaperone decouples TDP-43 disordered domain phase separation from fibrillation. Biochemistry 57506822–26
  130. 130. 
    Lin Y, Protter DS, Rosen MK, Parker R 2015. Formation and maturation of phase-separated liquid droplets by RNA-binding proteins. Mol. Cell 602208–19
  131. 131. 
    Lau HK, Paul A, Sidhu I, Li L, Sabanayagam CR 2018. Microstructured elastomer-PEG hydrogels via kinetic capture of aqueous liquid–liquid phase separation. Adv. Sci. 561701010
  132. 132. 
    Kaur T, Alshareedah I, Wang W, Ngo J, Moosa MM, Banerjee PR 2019. Molecular crowding tunes material states of ribonucleoprotein condensates. Biomolecules 92E71
  133. 133. 
    Reed EH, Hammer DA 2018. Redox sensitive protein droplets from recombinant oleosin. Soft Matter 14316506–13
  134. 134. 
    Kato M, Yang Y-S, Sutter BM, Wang Y, McKnight SL, Tu BP 2019. Redox state controls phase separation of the yeast ataxin-2 protein via reversible oxidation of its methionine-rich low-complexity domain. Cell 1773711–21
  135. 135. 
    Miyazawa S, Jernigan RL 1996. Residue-residue potentials with a favourable contact pair term and an unfavourable high packing density term, for simulation and threading. J. Mol. Biol. 256623–44
  136. 136. 
    Du H, Hu X, Duan H, Yu L, Qu F 2019. Principles of inter-amino-acid recognition revealed by binding energies between homogeneous oligopeptides. ACS Cent. Sci. 5197–108
  137. 137. 
    Dias CL, Chan HS 2014. Pressure-dependent properties of elementary hydrophobic interactions: ramifications for activation properties of protein folding. J. Phys. Chem B 118277488–509
  138. 138. 
    Winter RHA, Cinar H, Fetahaj Z, Cinar S, Vernon RM, Chan HS 2019. Temperature, hydrostatic pressure, and osmolyte effects on liquid-liquid phase separation in protein condensates: physical chemistry and biological implications. Chem. Eur. J. 255713049–69
  139. 139. 
    Banani SF, Rice AM, Peeples WB, Lin Y, Jain S 2016. Compositional control of phase-separated cellular bodies. Cell 1663651–63
  140. 140. 
    Rao BS, Parker R 2017. Numerous interactions act redundantly to assemble a tunable size of P bodies in Saccharomyces cerevisiae. PNAS 11445E9569–78
  141. 141. 
    Jacobs WM, Frenkel D 2017. Phase transitions in biological systems with many components. Biophys. J. 1124683–91
  142. 142. 
    Yoshizawa T, Ali R, Jiou J, Fung HYJ, Burke KA 2018. Nuclear import receptor inhibits phase separation of FUS through binding to multiple sites. Cell 1733693–705
  143. 143. 
    Maharana S, Wang J, Papadopoulos DK, Richter D, Pozniakovsky A 2018. RNA buffers the phase separation behavior of prion-like RNA binding proteins. Science 3606391918–21
  144. 144. 
    Banerjee PR, Milin AN, Moosa MM, Onuchic PL, Deniz AA 2017. Reentrant phase transition drives dynamic substructure formation in ribonucleoprotein droplets. Angew. Chem. Int. Ed. 563811354–59
  145. 145. 
    Boeynaems S, Holehouse AS, Weinhardt V, Kovacs D, Van Lindt J 2019. Spontaneous driving forces give rise to protein–RNA condensates with coexisting phases and complex material properties. PNAS 116167889–98
  146. 146. 
    Harmon TS, Holehouse AS, Pappu RV 2018. Differential solvation of intrinsically disordered linkers drives the formation of spatially organized droplets in ternary systems of linear multivalent proteins. New J. Phys. 204045002
  147. 147. 
    Rosenzweig ESF, Xu B, Cuellar LK, Martinez-Sanchez A, Schaffer M 2017. The eukaryotic CO2-concentrating organelle is liquid-like and exhibits dynamic reorganization. Cell 1711148–62
  148. 148. 
    Delarue M, Brittingham GP, Pfeffer S, Surovtsev I, Pinglay S 2018. mTORC1 controls phase separation and the biophysical properties of the cytoplasm by tuning crowding. Cell 1742338–49
  149. 149. 
    Wan G, Fields BD, Spracklin G, Shukla A, Phillips CM, Kennedy S 2018. Spatiotemporal regulation of liquid-like condensates in epigenetic inheritance. Nature 5577707679–83
  150. 150. 
    Feric M, Vaidya N, Harmon TS, Mitrea DM, Zhu L 2016. Coexisting liquid phases underlie nucleolar subcompartments. Cell 16571686–97
  151. 151. 
    Gasior K, Zhao J, McLaughlin G, Forest MG, Gladfelter AS, Newby J 2019. Partial demixing of RNA-protein complexes leads to intradroplet patterning in phase-separated biological condensates. Phys. Rev. E 991012411
  152. 152. 
    Fei J, Jadaliha M, Harmon TS, Li IT, Hua B 2017. Quantitative analysis of multilayer organization of proteins and RNA in nuclear speckles at super resolution. J. Cell Sci. 130244180–92
  153. 153. 
    Zheng W, Dignon G, Brown M, Kim YC, Mittal J 2020. Hydropathy patterning complements charge patterning to describe conformational preferences of disordered proteins. bioRxiv 919498. https://doi.org/10.1101/2020.01.25.919498
    [Crossref]
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