Phase separation in synthetic biology

Shi Shuyu , Si Wen , Ouyang Xiaoyi , Wei Ping

Quant. Biol. ›› 2021, Vol. 9 ›› Issue (4) : 378 -399.

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Quant. Biol. ›› 2021, Vol. 9 ›› Issue (4) : 378 -399. DOI: 10.15302/J-QB-021-0262
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Phase separation in synthetic biology

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Abstract

Background: The concept of phase separation has been used to describe and interpret physicochemical phenomena in biological systems for decades. Many intracellular macromolecules undergo phase separation, where it plays important roles in gene regulation, cellular signaling, metabolic reactions and so on, due to its unique dynamic properties and biological effects. As the noticeable importance of phase separation, pioneer researchers have explored the possibility to introduce the synthetically engineered phase separation for applicable cell function.

Results: In this article, we illustrated the application value of phase separation in synthetic biology. We described main states of phase separation in detail, summarized some ways to implement synthetic condensates and several methods to regulate phase separation, and provided a substantial amount of identical examples to illuminate the applications and perspectives of phase separation in synthetic biology.

Conclusions: Multivalent interactions implement phase separation in synthetic biology. Small molecules, light control and spontaneous interactions induce and regulate phase separation. The synthetic condensates are widely used in signal amplifications, designer orthogonally non-membrane-bound organelles, metabolic pathways, gene regulations, signaling transductions and controllable platforms. Studies on quantitative analysis, more standardized modules and precise spatiotemporal control of synthetic phase separation may promote the further development of this field.

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Keywords

phase separation / synthetic biology / multivalent interaction / non-membrane-bound organelle / signaling transduction and amplification

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Shi Shuyu, Si Wen, Ouyang Xiaoyi, Wei Ping. Phase separation in synthetic biology. Quant. Biol., 2021, 9(4): 378-399 DOI:10.15302/J-QB-021-0262

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References

[1]

MitreaD. M. , Kriwacki, R. W.. Phase separation in biology; functional organization of a higher order. Cell Commun. Signal., 2016, 14 : 1–

[2]

HymanA. A., Weber, C. A. , Jülicher, F.. Liquid-liquid phase separation in biology. Annu. Rev. Cell Dev. Biol., 2014, 30 : 39– 58

[3]

LuzioJ. P., Pryor, P. R. , Bright, N. A.. Lysosomes: fusion and function. Nat. Rev. Mol. Cell Biol., 2007, 8 : 622– 632

[4]

FriedmanJ. R. , Nunnari, J.. Mitochondrial form and function. Nature, 2014, 505 : 335– 343

[5]

BoisvertF.-M., van Koningsbruggen, S., Navascués, J. , Lamond, A. I.. The multifunctional nucleolus. Nat. Rev. Mol. Cell Biol., 2007, 8 : 574– 585

[6]

BuchanJ. R. , Parker, R.. Eukaryotic stress granules: the ins and outs of translation. Mol. Cell, 2009, 36 : 932– 941

[7]

DeckerC. J. , Parker, R.. P-bodies and stress granules: possible roles in the control of translation and mRNA degradation. Cold Spring Harb. Perspect. Biol., 2012, 4 : a012286–

[8]

BrangwynneP., C.R., EckmannS., C.A. Germline P granules are liquid droplets that localize by controlled dissolution/condensation. Science, 2009, 324 : 1729– 1732

[9]

BoeynaemsL., S.Den Bosch. Protein phase separation: a new phase in cell biology. Trends Cell Biol., 2018, 28 : 420– 435

[10]

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

[11]

BerryJ., Brangwynne, C. P. , Haataja, M.. Physical principles of intracellular organization via active and passive phase transitions. Rep. Prog. Phys., 2018, 81 : 046601–

[12]

WilsonE. B.. The structure of protoplasm. Science, 1899, 10 : 33– 45

[13]

TangL.. Liquid phase separation. Nat. Methods, 2019, 16 : 18–

[14]

ZhangH., Ji, X., Li, P., Liu, C., Lou, J., Wang, Z., Wen, W., Xiao, Y., Zhang, M. , Zhu, X.. Liquid-liquid phase separation in biology: mechanisms, physiological functions and human diseases. Sci. China Life Sci., 2020, 63 : 953– 985

[15]

GoodrichJ. , Taatjes, D.. Transcription regulation enters a new phase. Nature, 2018, 558 : 197– 198

[16]

HarlenK. M. , Churchman, L. S.. The code and beyond: transcription regulation by the RNA polymerase II carboxy-terminal domain. Nat. Rev. Mol. Cell Biol., 2017, 18 : 263– 273

[17]

LuH., Yu, D., Hansen, A. S., Ganguly, S., Liu, R., Heckert, A., Darzacq, X. , Zhou, Q.. Phase-separation mechanism for C-terminal hyperphosphorylation of RNA polymerase II. Nature, 2018, 558 : 318– 323

[18]

WeiM.-T., Chang, Y.-C., Shimobayashi, S. F., Shin, Y., Strom, A. R. , Brangwynne, C. P.. Nucleated transcriptional condensates amplify gene expression. Nat. Cell Biol., 2020, 22 : 1187– 1196

[19]

ZaborowskaJ., Egloff, S. , Murphy, S.. The pol II CTD: new twists in the tail. Nat. Struct. Mol. Biol., 2016, 23 : 771– 777

[20]

BoijaA., A.R., KleinL., I.V., SabariH., B.C.and Hannett, Dall’AgneseM. Transcription factors activate genes through the phase-separation capacity of their activation domains. Cell, 2018, 175 : 1842– 1855.e16

[21]

GuoE., Y.C., ManteigaE., J.R., HenningerM., J.K., SabariV.. Pol II phosphorylation regulates a switch between transcriptional and splicing condensates. Nature, 2019, 572 : 543– 548

[22]

SabariR., B.A., Dall’AgneseL., A.J., BoijaM., A.V., KleinC.. Coactivator condensation at super-enhancers links phase separation and gene control. Science, 2018, 361 : eaar3958–

[23]

ZuoL., Zhang, G., Massett, M., Cheng, J., Guo, Z., Wang, L., Gao, Y., Li, R., Huang, X., Li, P.. Loci-specific phase separation of FET fusion oncoproteins promotes gene transcription. Nat. Commun., 2021, 12 : 1491–

[24]

ErdelF. , Rippe, K.. Formation of chromatin subcompartments by phase separation. Biophys. J., 2018, 114 : 2262– 2270

[25]

NarlikarG. J.. Phase-separation in chromatin organization. J. Biosci., 2020, 45 : 5–

[26]

PalikyrasS. , Papantonis, A.. Modes of phase separation affecting chromatin regulation. Open Biol., 2019, 9 : 190167–

[27]

LarsonG., A.M., ElnatanJ., D.B., KeenenL., M.A., TrnkaJ. Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature, 2017, 547 : 236– 240

[28]

StromA. R., Emelyanov, A. V., Mir, M., Fyodorov, D. V., Darzacq, X. , Karpen, G. H.. Phase separation drives heterochromatin domain formation. Nature, 2017, 547 : 241– 245

[29]

YoshizawaT., Nozawa, R. S., Jia, T. Z., Saio, T. , Mori, E.. Biological phase separation: cell biology meets biophysics. Biophys. Rev., 2020, 12 : 519– 539

[30]

GibsonA., B.K., DoolittleW., L.E., SchneiderW., M.K. Organization of chromatin by intrinsic and regulated phase separation. Cell, 2019, 179 : 470– 484.e21

[31]

BeckerJ. S., Nicetto, D. , Zaret, K. S.. H3K9me3-dependent heterochromatin: barrier to cell fate changes. Trends Genet., 2016, 32 : 29– 41

[32]

KilicS., Bachmann, A. L., Bryan, L. C. , Fierz, B.. Multivalency governs HP1α association dynamics with the silent chromatin state. Nat. Commun., 2015, 6 : 7313–

[33]

WangL., Gao, Y., Zheng, X., Liu, C., Dong, S., Li, R., Zhang, G., Wei, Y., Qu, H., Li, Y.. Histone modifications regulate chromatin compartmentalization by contributing to a phase separation mechanism. Mol. Cell, 2019, 76 : 646– 659

[34]

WeiC., Cheng, J., Zhou, B., Zhu, L., Khan, M. A., He, T., Zhou, S., He, J., Lu, X., Chen, H.. Tripartite motif containing 28 (TRIM28) promotes breast cancer metastasis by stabilizing TWIST1 protein. Sci. Rep., 2016, 6 : 29822–

[35]

SanulliJ., S.W., TrnkaD., M.L., DharmarajanR., V.D., TibbleJ. HP1 reshapes nucleosome core to promote phase separation of heterochromatin. Nature, 2019, 575 : 390– 394

[36]

BannisterA. J., Zegerman, P., Partridge, J. F., Miska, E. A., Thomas, J. O., Allshire, R. C. , Kouzarides, T.. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature, 2001, 410 : 120– 124

[37]

GrewalS. I., Moazed, D.. Heterochromatin and epigenetic control of gene expression. Science, 2003, 301 : 798– 802

[38]

ZhangW., Liu, W., Jia, L., Chen, D., Chang, I., Lake, M., Bentolila, L. A. , Wang, C. Y.. Targeting KDM4A epigenetically activates tumor-cell-intrinsic immunity by inducing DNA replication stress. Mol. Cell, 2021, 81 : 2148– 2165

[39]

ShakyaA., Park, S., Rana, N. , King, J. T.. Liquid-liquid phase separation of histone proteins in cells: role in chromatin organization. Biophys. J., 2020, 118 : 753– 764

[40]

BrewerC. F., Miceli, M. C. , Baum, L. G.. Clusters, bundles, arrays and lattices: novel mechanisms for lectin-saccharide-mediated cellular interactions. Curr. Opin. Struct. Biol., 2002, 12 : 616– 623

[41]

CaseL. B., Ditlev, J. A. , Rosen, M. K.. Regulation of transmembrane signaling by phase separation. Annu. Rev. Biophys., 2019, 48 : 465– 494

[42]

CaseL. B., Zhang, X., Ditlev, J. A. , Rosen, M. K.. Stoichiometry controls activity of phase-separated clusters of actin signaling proteins. Science, 2019, 363 : 1093– 1097

[43]

HoutmanC., J.L.. Binding specificity of multiprotein signaling complexes is determined by both cooperative interactions and affinity preferences. Biochemistry, 2004, 43 : 4170– 4178

[44]

HuangY. C., W.K., AlvarezK., S.Y. M., KondoH., Y.T. A molecular assembly phase transition and kinetic proofreading modulate Ras activation by SOS. Science, 2019, 363 : 1098– 1103

[45]

KimS., Kalappurakkal, J. M., Mayor, S. , Rosen, M. K.. Phosphorylation of Nephrin induces phase separated domains that move through actomyosin contraction. Mol. Biol. Cell., 2019, 30 : 2996– 3012

[46]

DuM. , Chen, Z. J.. DNA-induced liquid phase condensation of cGAS activates innate immune signaling. Science, 2018, 361 : 704– 709

[47]

YooH., Triandafillou, C. , Drummond, D. A.. Cellular sensing by phase separation: Using the process, not just the products. J. Biol. Chem., 2019, 294 : 7151– 7159

[48]

BurdetteD. L. , Vance, R. E.. STING and the innate immune response to nucleic acids in the cytosol. Nat. Immunol., 2013, 14 : 19– 26

[49]

AcunaC., Liu, X. , Südhof, T. C.. How to make an active zone: unexpected universal functional redundancy between RIMs and RIM-BPs. Neuron, 2016, 91 : 792– 807

[50]

MittelstaedtT., Alvaréz-Baron, E. , Schoch, S.. RIM proteins and their role in synapse function. Biol. Chem., 2010, 391 : 599– 606

[51]

WuX., Cai, Q., Shen, Z., Chen, X., Zeng, M., Du, S. , Zhang, M.. RIM and RIM-BP form presynaptic active-zone-like condensates via phase separation. Mol. Cell, 2019, 73 : 971– 984.e5

[52]

ZengM., Chen, X., Guan, D., Xu, J., Wu, H., Tong, P. , Zhang, M.. Reconstituted postsynaptic density as a molecular platform for understanding synapse formation and plasticity. Cell, 2018, 174 : 1172– 1187.e16

[53]

ZengM., Shang, Y., Araki, Y., Guo, T., Huganir, R. L. , Zhang, M.. Phase transition in postsynaptic densities underlies formation of synaptic complexes and synaptic plasticity. Cell, 2016, 166 : 1163– 1175.e12

[54]

AguzziA. , Altmeyer, M.. Phase separation: linking cellular compartmentalization to disease. Trends Cell Biol., 2016, 26 : 547– 558

[55]

BhopatkarA. A., Uversky, V. N. , Rangachari, V.. Granulins modulate liquid-liquid phase separation and aggregation of prion-like C-terminal domain of the neurodegeneration-associated protein TDP-43. J. Biol., Chem., 2020, 295 : 2506– 2519

[56]

ConicellaA. E., Zerze, G. H., Mittal, J. , Fawzi, N. L.. ALS mutations disrupt phase separation mediated by α-helical structure in the TDP-43 low-complexity C-terminal domain. Structure, 2016, 24 : 1537– 1549

[57]

PatelO., A.Y., LeeM.. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell, 2015, 162 : 1066– 1077

[58]

AmbadipudiS., Biernat, J., Riedel, D., Mandelkow, E. , Zweckstetter, M.. Liquid-liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau. Nat. Commun., 2017, 8 : 275–

[59]

GustkeN., Trinczek, B., Biernat, J., Mandelkow, E.-M. , Mandelkow, E.. Domains of tau protein and interactions with microtubules. Biochemistry, 1994, 33 : 9511– 9522

[60]

WegmannM., S.E., EftekharzadehR.. Tau protein liquid-liquid phase separation can initiate tau aggregation. EMBO J., 2018, 37 : e98049–

[61]

Bergeron-SandovalW. Mechanisms and consequences of macromolecular phase separation. Cell, 2016, 165 : 1067– 1079

[62]

CableV., J.A., BrangwynneE.. Phase separation in biology and disease-a symposium report. Ann. N. Y. Acad. Sci., 2019, 1452 : 3– 11

[63]

ZbindenA., Pérez-Berlanga, M., De Rossi, P. , Polymenidou, M.. Phase separation and neurodegenerative diseases: A disturbance in the force. Dev. Cell, 2020, 55 : 45– 68

[64]

MutschlerH., Robinson, T., Tang, T. D. , Wegner, S.. Special issue on bottom-up synthetic biology. ChemBioChem, 2019, 20 : 2533– 2534

[65]

AndrianantoandroE., Basu, S., Karig, D. K. , Weiss, R.. Synthetic biology: new engineering rules for an emerging discipline. Mol. Syst. Biol., 2006, 2 : 2006.0028–

[66]

SchwilleP.. Bottom-up synthetic biology: engineering in a tinkerer’s world. Science, 2011, 333 : 1252– 1254

[67]

BennerS. A. , Sismour, A. M.. Synthetic biology. Nat. Rev. Genet., 2005, 6 : 533– 543

[68]

Oparin, A. (1953) The Origin of Life. 2nd ed. New York: Dover

[69]

PoudyalR. R., Pir Cakmak, F., Keating, C. D. , Bevilacqua, P. C.. Physical principles and extant biology reveal roles for RNA-containing membraneless compartments in origins of life chemistry. Biochemistry, 2018, 57 : 2509– 2519

[70]

HastingsR. L. , Boeynaems, S.. Designer condensates: A toolkit for the biomolecular architect. J. Mol. Biol., 2021, 433 : 166837–

[71]

AlbertiS., Gladfelter, A. , Mittag, T.. Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates. Cell, 2019, 176 : 419– 434

[72]

RibackA., J.C., ZhuM., L.W., FerrolinoT., M.W., TolbertP. Composition-dependent thermodynamics of intracellular phase separation. Nature, 2020, 581 : 209– 214

[73]

ShinY. , Brangwynne, C. P.. Liquid phase condensation in cell physiology and disease. Science, 2017, 357 : eaaf4382–

[74]

JonesR. , Weitz, D.. Soft Condensed Matter. Phys. Today, 2003, 56 : 63– 64

[75]

BabinchakW. M. , Surewicz, W. K.. Liquid-liquid phase separation and its mechanistic role in pathological protein aggregation. J. Mol. Biol., 2020, 432 : 1910– 1925

[76]

SunY., Zhao, K., Xia, W., Feng, G., Gu, J., Ma, Y., Gui, X., Zhang, X., Fang, Y., Sun, B.. The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure. Nat. Commun., 2020, 11 : 6349–

[77]

KanaanN. M., Hamel, C., Grabinski, T. , Combs, B.. Liquid-liquid phase separation induces pathogenic tau conformations in vitro. Nat. Commun., 2020, 11 : 2809–

[78]

AlbertiS.. Phase separation in biology. Curr. Biol., 2017, 27 : R1097– R1102

[79]

FranzmannM., T.S., JahnelW., M.V.. Phase separation of a yeast prion protein promotes cellular fitness. Science, 2018, 359 : eaao5654–

[80]

NottJ., T.D., PetsalakiP., E.D.. Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. Mol. Cell, 2015, 57 : 936– 947

[81]

RuffK. M., Roberts, S., Chilkoti, A. , Pappu, R. V.. Advances in understanding stimulus-responsive phase behavior of intrinsically disordered protein polymers. J. Mol. Biol., 2018, 430 : 4619– 4635

[82]

MohammadiV. I., P.P. J., JonkergouwB. Controllable coacervation of recombinantly produced spider silk protein using kosmotropic salts. J. Colloid Interface Sci., 2020, 560 : 149– 160

[83]

DaoP., T.J., KolaitisP., R.-M.A. Ubiquitin modulates liquid-liquid phase separation of UBQLN2 via disruption of multivalent interactions. Mol. Cell., 2018, 69 : 965– 978.e6

[84]

RaiA. K., Chen, J.-X., Selbach, M. , Pelkmans, L.. Kinase-controlled phase transition of membraneless organelles in mitosis. Nature, 2018, 559 : 211– 216

[85]

BananiS. F., Rice, A. M., Peeples, W. B., Lin, Y., Jain, S., Parker, R. , Rosen, M. K.. Compositional control of phase-separated cellular bodies. Cell, 2016, 166 : 651– 663

[86]

MittagT. , Parker, R.. Multiple modes of protein–protein interactions promote RNP granule assembly. J. Mol. Biol., 2018, 430 : 4636– 4649

[87]

StattA., Casademunt, H., Brangwynne, C. , Panagiotopoulos, A.. Model for intrinsically disordered proteins with a strong dependence of liquid-liquid phase separation on sequence. Bull. Am. Phys. Soc., 2020, 152 : 075101–

[88]

UverskyV. N.. Intrinsically disordered proteins in overcrowded milieu: Membrane-less organelles, phase separation, and intrinsic disorder. Curr. Opin. Struct. Biol., 2017, 44 : 18– 30

[89]

BrangwynneC. P., Tompa, P. , Pappu, R. V.. Polymer physics of intracellular phase transitions. Nat. Phys., 2015, 11 : 899– 904

[90]

Elbaum-GarfinkleC.-H., S.R., KimP. The disordered P granule protein LAF-1 drives phase separation into droplets with tunable viscosity and dynamics. Proc. Natl. Acad. Sci. USA, 2015, 112 : 7189– 7194

[91]

SmithJ., Calidas, D., Schmidt, H., Lu, T., Rasoloson, D. , Seydoux, G.. Spatial patterning of P granules by RNA-induced phase separation of the intrinsically-disordered protein MEG-3. eLife, 2016, 5 : e21337–

[92]

WangS., J.O.. A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins. Cell, 2018, 174 : 688– 699.e16

[93]

RibackA., J.D., KatanskiL., C.V., Kear-ScottE., J.R., PilipenkoA. Stress-triggered phase separation is an adaptive, evolutionarily tuned response. Cell, 2017, 168 : 1028– 1040.e19

[94]

ChongP. A., Vernon, R. M. , Forman-Kay, J. D.. RGG/RG motif regions in RNA binding and phase separation. J. Mol. Biol., 2018, 430 : 4650– 4665

[95]

ThandapaniP., O’Connor, T. R., Bailey, T. L. , Richard, S.. Defining the RGG/RG motif. Mol. Cell, 2013, 50 : 613– 623

[96]

ShinY., Berry, J., Pannucci, N., Haataja, M. P., Toettcher, J. E. , Brangwynne, C. P.. Spatiotemporal control of intracellular phase transitions using light-activated optoDroplets. Cell, 2017, 168 : 159– 171.e14

[97]

DueberE., J.C., WuR., G.S., MalmircheginiJ., G.V., MoonL., T.D. Synthetic protein scaffolds provide modular control over metabolic flux. Nat. Biotechnol., 2009, 27 : 753– 759

[98]

ReinkemeierC. D., Girona, G. E. , Lemke, E. A.. Designer membraneless organelles enable codon reassignment of selected mRNAs in eukaryotes. Science, 2019, 363 : eaaw2644–

[99]

MonahanH., Z.M., RyanA., V.N., JankeH., A.L., BurkeE.. Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity. EMBO J., 2017, 36 : 2951– 2967

[100]

QamarJ., S.S., WangA., G.Q., RandleC.. FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-π interactions. Cell, 2018, 173 : 720– 734.e15

[101]

HanT. W., Kato, M., Xie, S., Wu, L. C., Mirzaei, H., Pei, J., Chen, M., Xie, Y., Allen, J., Xiao, G.. Cell-free formation of RNA granules: bound RNAs identify features and components of cellular assemblies. Cell, 2012, 149 : 768– 779

[102]

KatoW., M.C., HanJ.. Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell, 2012, 149 : 753– 767

[103]

MurakamiQ., T.S. K., QamarR., S.B., LinT., J.H.. ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function. Neuron, 2015, 88 : 678– 690

[104]

MurthyA. C., Dignon, G. L., Kan, Y., Zerze, G. H., Parekh, S. H., Mittal, J. , Fawzi, N. L.. Molecular interactions underlying liquid-liquid phase separation of the FUS low-complexity domain. Nat. Struct. Mol. Biol., 2019, 26 : 637– 648

[105]

MurrayD. T., Kato, M., Lin, Y., Thurber, K. R., Hung, I., McKnight, S. L. , Tycko, R.. Structure of FUS protein fibrils and its relevance to self-assembly and phase separation of low-complexity domains. Cell, 2017, 171 : 615– 627.e16

[106]

ZhaoE. M., Suek, N., Wilson, M. Z., Dine, E., Pannucci, N. L., Gitai, Z., Avalos, J. L. , Toettcher, J. E.. Light-based control of metabolic flux through assembly of synthetic organelles. Nat. Chem. Biol., 2019, 15 : 589– 597

[107]

VernonR. M. , Forman-Kay, J. D.. First-generation predictors of biological protein phase separation. Curr. Opin. Struct. Biol., 2019, 58 : 88– 96

[108]

HughesP., M.R., SawayaR., M.A., BoyerS. Atomic structures of low-complexity protein segments reveal kinked β sheets that assemble networks. Science, 2018, 359 : 698– 701

[109]

KrainerJ., G.A., WelshR., T.A.. Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions. Nat. Commun., 2021, 12 : 1085–

[110]

PawlukA.. Breaking the Rules. Cell, 2018, 173 : 805– 807

[111]

FrazerI., C.A., StaplesV., M.D., KimH., Y.L., HirakawaJ.. Epigenetic cell fate in Candida albicans is controlled by transcription factor condensates acting at super-enhancer-like elements. Nat. Microbiol., 2020, 5 : 1374– 1389

[112]

BradyP., J.J., FarberJ., P.S., SekharJ., A.D.. Structural and hydrodynamic properties of an intrinsically disordered region of a germ cell-specific protein on phase separation. Proc. Natl. Acad. Sci. USA, 2017, 114 : E8194– E8203

[113]

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

[114]

BanjadeS. , Rosen, M. K.. Phase transitions of multivalent proteins can promote clustering of membrane receptors. eLife, 2014, 3 : e04123–

[115]

BanjadeS., Wu, Q., Mittal, A., Peeples, W. B., Pappu, R. V. , Rosen, M. K.. Conserved interdomain linker promotes phase separation of the multivalent adaptor protein Nck. Proc. Natl. Acad. Sci. USA, 2015, 112 : E6426– E6435

[116]

LiV., P.S., BanjadeF.. Phase transitions in the assembly of multivalent signalling proteins. Nature, 2012, 483 : 336– 340

[117]

ShenB., Chen, Z., Yu, C., Chen, T., Shi, M. , Li, T.. Computational screening of biological phase-separating proteins. Genom. Proteom. Bioinform., 2021, S1672– 0229(21)00022-X

[118]

LinY., Protter, D. S., Rosen, M. K. , Parker, R.. Formation and maturation of phase-separated liquid droplets by RNA-binding proteins. Mol. Cell, 2015, 60 : 208– 219

[119]

WoolfsonD. N., Bartlett, G. J., Burton, A. J., Heal, J. W., Niitsu, A., Thomson, A. R. , Wood, C. W.. De novo protein design: how do we expand into the universe of possible protein structures?. Curr. Opin. Struct. Biol., 2015, 33 : 16– 26

[120]

HuangY., P.-S.L., OberdorferM.. High thermodynamic stability of parametrically designed helical bundles. Science, 2014, 346 : 481– 485

[121]

ThomsonA. R., Wood, C. W., Burton, A. J., Bartlett, G. J., Sessions, R. B., Brady, R. L. , Woolfson, D. N.. Computational design of water-soluble α-helical barrels. Science, 2014, 346 : 485– 488

[122]

ZhangR., Q.B. Visualizing dynamics of cell signaling in vivo with a phase separation-based kinase reporter. Mol. Cell, 2018, 69 : 334– 346.e4

[123]

SchusterS., B.H., ReedN., E.M., ParthasarathyG., R.C., JahnkeA. Controllable protein phase separation and modular recruitment to form responsive membraneless organelles. Nat. Commun., 2018, 9 : 2985–

[124]

KolarK. , Weber, W.. Synthetic biological approaches to optogenetically control cell signaling. Curr. Opin. Biotechnol., 2017, 47 : 112– 119

[125]

TangL.. Optogenetic tools light up phase separation. Nat. Methods, 2019, 16 : 139–

[126]

LiY.-J., Stark, J. M., Chen, D. J., Ann, D. K. , Chen, Y.. Role of SUMO: SIM-mediated protein-protein interaction in non-homologous end joining. Oncogene, 2010, 29 : 3509– 3518

[127]

HusnjakK., Keiten-Schmitz, J. , Müller, S.. Identification and characterization of SUMO-SIM interactions. Methods Mol. Biol., 2016, 1475 : 79– 98

[128]

ParkR., S.-Y.C. Abscisic acid inhibits type 2C protein phosphatases via the PYR/PYL family of START proteins. Science, 2009, 324 : 1068– 1071

[129]

YinP., Fan, H., Hao, Q., Yuan, X., Wu, D., Pang, Y., Yan, C., Li, W., Wang, J. , Yan, N.. Structural insights into the mechanism of abscisic acid signaling by PYL proteins. Nat. Struct. Mol. Biol., 2009, 16 : 1230– 1236

[130]

LumbaS., Cutler, S. , McCourt, P.. Plant nuclear hormone receptors: a role for small molecules in protein-protein interactions. Annu. Rev. Cell Dev. Biol., 2010, 26 : 445– 469

[131]

WheelerJ., R.O., LeeN., H.C. Small molecules for modulating protein driven liquid-liquid phase separation in treating neurodegenerative disease. bioRxiv, 2019, 721001–

[132]

YangX., Jost, A. P.-T., Weiner, O. D. , Tang, C.. A light-inducible organelle-targeting system for dynamically activating and inactivating signaling in budding yeast. Mol. Biol. Cell, 2013, 24 : 2419– 2430

[133]

BrachaD., Walls, M. T., Wei, M.-T., Zhu, L., Kurian, M., Avalos, J. L., Toettcher, J. E. , Brangwynne, C. P.. Mapping local and global liquid phase behavior in living cells using photo-oligomerizable seeds. Cell, 2018, 175 : 1467– 1480.e13

[134]

DineE., Gil, A. A., Uribe, G., Brangwynne, C. P. , Toettcher, J. E.. Protein phase separation provides long-term memory of transient spatial stimuli. Cell Syst., 2018, 6 : 655– 663.e5

[135]

ShinS., Y.W., ChangS., Y.-C.P. Liquid nuclear condensates mechanically sense and restructure the genome. Cell, 2018, 175 : 1481– 1491.e13

[136]

SchneiderN., Wieland, F.-G., Kong, D., Fischer, A. A. M., Hörner, M., Timmer, J., Ye, H. , Weber, W.. Liquid-liquid phase separation of light-inducible transcription factors increases transcription activation in mammalian cells and mice. Sci. Adv., 2021, 7 : eabd3568–

[137]

BuckleyC. E., Moore, R. E., Reade, A., Goldberg, A. R., Weiner, O. D. , Clarke, J. D. W.. Reversible optogenetic control of subcellular protein localization in a live vertebrate embryo. Dev. Cell, 2016, 36 : 117– 126

[138]

ReedE. H., Schuster, B. S., Good, M. C. , Hammer, D. A.. SPLIT: stable protein coacervation using a light induced transition. ACS Synth. Biol., 2020, 9 : 500– 507

[139]

DolginE.. Cell biology’s new phase. Nature, 2018, 555 : 300– 302

[140]

ZhaoY. G. , Zhang, H.. Phase separation in membrane biology: The interplay between membrane-bound organelles and membraneless condensates. Dev. Cell, 2020, 55 : 30– 44

[141]

MaW., MayrC.. A membraneless organelle associated with the endoplasmic reticulum enables 3′ UTR-mediated protein-protein interactions. Cell, 2018, 175 : 1492– 1506.e19

[142]

ProuteauM. , Loewith, R.. Regulation of cellular metabolism through phase separation of enzymes. Biomolecules, 2018, 8 : 160–

[143]

CastellanaM., Wilson, M. Z., Xu, Y., Joshi, P., Cristea, I. M., Rabinowitz, J. D., Gitai, Z. , Wingreen, N. S.. Enzyme clustering accelerates processing of intermediates through metabolic channeling. Nat. Biotechnol., 2014, 32 : 1011– 1018

[144]

LiuM., He, S., Cheng, L., Qu, J. , Xia, J.. Phase-separated multienzyme biosynthesis. Biomacromolecules, 2020, 21 : 2391– 2399

[145]

PiccinnoR., Minneker, V. , Roukos, V.. 53BP1-DNA repair enters a new liquid phase. EMBO J., 2019, 38 : e102871–

[146]

JacksonS. P. , Bartek, J.. The DNA-damage response in human biology and disease. Nature, 2009, 461 : 1071– 1078

[147]

PanierS. , Boulton, S. J.. Double-strand break repair: 53BP1 comes into focus. Nat. Rev. Mol. Cell Biol., 2014, 15 : 7– 18

[148]

SchwertmanP., Bekker-Jensen, S. , Mailand, N.. Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers. Nat. Rev. Mol. Cell Biol., 2016, 17 : 379– 394

[149]

WilsonM. D. , Durocher, D.. Reading chromatin signatures after DNA double-strand breaks. Philos. Trans. R. Soc. Lond. B Biol. Sci., 2017, 372 : 20160280–

[150]

KilicS., Lezaja, A., Gatti, M., Bianco, E., Michelena, J., Imhof, R. , Altmeyer, M.. Phase separation of 53BP1 determines liquid-like behavior of DNA repair compartments. EMBO J., 2019, 38 : e101379–

[151]

Pessina. Functional transcription promoters at DNA double-strand breaks mediate RNA-driven phase separation of damage-response factors. Nat. Cell Biol., 2019, 21 : 1286– 1299

[152]

LieberM. R.. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu. Rev. Biochem., 2010, 79 : 181– 211

[153]

HeyerW.-D., Ehmsen, K. T. , Liu, J.. Regulation of homologous recombination in eukaryotes. Annu. Rev. Genet., 2010, 44 : 113– 139

[154]

ChapmanJ. R., Taylor, M. R. , Boulton, S. J.. Playing the end game: DNA double-strand break repair pathway choice. Mol. Cell, 2012, 47 : 497– 510

[155]

GossenM. , Bujard, H.. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc. Natl. Acad. Sci. USA, 1992, 89 : 5547– 5551

[156]

SimonJ. R., Eghtesadi, S. A., Dzuricky, M., You, L. , Chilkoti, A.. Engineered ribonucleoprotein granules inhibit translation in protocells. Mol. Cell, 2019, 75 : 66– 75

[157]

McDanielJ. R., Radford, D. C. , Chilkoti, A.. A unified model for de novo design of elastin-like polypeptides with tunable inverse transition temperatures. Biomacromolecules, 2013, 14 : 2866– 2872

[158]

RauscherS. , Pomès, R.. The liquid structure of elastin. eLife, 2017, 6 : e26526–

[159]

RobertsS., Dzuricky, M. , Chilkoti, A.. Elastin-like polypeptides as models of intrinsically disordered proteins. FEBS Lett., 2015, 589 : 2477– 2486

[160]

DuanT. , Li, H.. In situ phase transition of elastin-like polypeptide chains regulates thermoresponsive properties of elastomeric protein-based hydrogels. Biomacromolecules, 2020, 21 : 2258– 2267

[161]

TruongA. T., Hamada, K., Yamada, Y., Guo, H., Kikkawa, Y., Okamoto, C. T., MacKay, J. A. , Nomizu, M.. Evaluation of extracellular matrix mimetic laminin bioactive peptide and elastin-like polypeptide. FASEB J., 2020, 34 : 6729– 6740

[162]

ChungH. K., Zou, X., Bajar, B. T., Brand, V. R., Huo, Y., Alcudia, J. F., Ferrell, J. E. Jr , Lin, M. Z.. A compact synthetic pathway rewires cancer signaling to therapeutic effector release. Science, 2019, 364 : eaat6982–

[163]

RickertR. C.. New insights into pre-BCR and BCR signalling with relevance to B cell malignancies. Nat. Rev. Immunol., 2013, 13 : 578– 591

[164]

StricklandM., D.R., LinL.. TULIPs: tunable, light-controlled interacting protein tags for cell biology. Nat. Methods, 2012, 9 : 379– 384

[165]

McSwiggenD. T., Mir, M., Darzacq, X. , Tjian, R.. Evaluating phase separation in live cells: diagnosis, caveats, and functional consequences. Genes Dev., 2019, 33 : 1619– 1634

[166]

NarayananA., Meriin, A., Andrews, J. O., Spille, J.-H., Sherman, M. Y. , Cisse, I. I.. A first order phase transition mechanism underlies protein aggregation in mammalian cells. eLife, 2019, 8 : e39695–

[167]

JawerthL. M., Ijavi, M., Ruer, M., Saha, S., Jahnel, M., Hyman, A. A., Jülicher, F. , Fischer-Friedrich, E.. Salt-dependent rheology and surface tension of protein condensates using optical traps. Phys. Rev. Lett., 2018, 121 : 258101–

[168]

YangX., Wei, J., Wang, Y., Yang, C., Zhao, S., Li, C., Dong, Y., Bai, K., Li, Y., Teng, H.. A genetically encoded protein polymer for uranyl binding and extraction based on the SpyTag-SpyCatcher chemistry. ACS Synth. Biol., 2018, 7 : 2331– 2339

[169]

VernonR. M., Chong, P. A., Tsang, B., Kim, T. H., Bah, A., Farber, P., Lin, H. , Forman-Kay, J. D.. Pi-Pi contacts are an overlooked protein feature relevant to phase separation. eLife, 2018, 7 : e31486–

[170]

MartinE. W. , Mittag, T.. Relationship of sequence and phase separation in protein low-complexity regions. Biochemistry, 2018, 57 : 2478– 2487

[171]

NingW., Guo, Y., Lin, S., Mei, B., Wu, Y., Jiang, P., Tan, X., Zhang, W., Chen, G., Peng, D.. DrLLPS: a data resource of liquid-liquid phase separation in eukaryotes. Nucleic Acids Res., 2020, 48 : D288– D295

[172]

LiQ., Peng, X., Li, Y., Tang, W., Zhu, J., Huang, J., Qi, Y. , Zhang, Z.. LLPSDB: a database of proteins undergoing liquid-liquid phase separation in vitro. Nucleic Acids Res., 2020, 48 : D320– D327

[173]

YouK., Huang, Q., Yu, C., Shen, B., Sevilla, C., Shi, M., Hermjakob, H., Chen, Y. , Li, T.. PhaSepDB: a database of liquid-liquid phase separation related proteins. Nucleic Acids Res., 2020, 48 : D354– D359

[174]

MészárosP.. PhaSePro: the database of proteins driving liquid-liquid phase separation. Nucleic Acids Res, 2020, 48 : D360– D367

[175]

SunT., Li, Q., Xu, Y., Zhang, Z., Lai, L. , Pei, J.. Prediction of liquid-liquid phase separation proteins using machine learning. bioRxiv, 2019, 842336–

[176]

FericS., M.M., VaidyaM., N.W., HarmonV., T.P. Coexisting liquid phases underlie nucleolar subcompartments. Cell, 2016, 165 : 1686– 1697

[177]

ZhuL. , Brangwynne, C. P.. Nuclear bodies: the emerging biophysics of nucleoplasmic phases. Curr. Opin. Cell Biol., 2015, 34 : 23– 30

[178]

GogliaA. G. , Toettcher, J. E.. A bright future: optogenetics to dissect the spatiotemporal control of cell behavior. Curr. Opin. Chem. Biol., 2019, 48 : 106– 113

[179]

WilsonM. Z., Ravindran, P. T., Lim, W. A. , Toettcher, J. E.. Tracing information flow from Erk to target gene induction reveals mechanisms of dynamic and combinatorial control. Mol. cell, 2017, 67 : 757– 769.e5

[180]

Krawczyk. Electrogenetic cellular insulin release for real-time glycemic control in type 1 diabetic mice. Science, 2020, 368 : 993– 1001

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