Home LiteratureArticle Details
PMID: 31694155 Published · epublish English Journal Article Review

The Role of Post-Translational Modifications in the Phase Transitions of Intrinsically Disordered Proteins.

International journal of molecular sciences ·Vol. 20 ·No. 21 ·2019-11-05

Owen I, Shewmaker F

Abstract

Advances in genomics and proteomics have revealed eukaryotic proteomes to be highly abundant in intrinsically disordered proteins that are susceptible to diverse post-translational modifications. Intrinsically disordered regions are critical to the liquid-liquid phase separation that facilitates specialized cellular functions. Here, we discuss how post-translational modifications of intrinsically disordered protein segments can regulate the molecular condensation of macromolecules into functional phase-separated complexes.

Keywords
intrinsically disordered regions liquid–liquid phase separation membraneless organelles post-translational modifications
MeSH Terms
Animals Humans Intrinsically Disordered Proteins/chemistry,metabolism Neurodegenerative Diseases/metabolism Phase Transition Protein Domains Protein Processing, Post-Translational
Chemicals
Intrinsically Disordered Proteins
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Owen Izzy
Department of Biochemistry, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Shewmaker Frank ORCID
Department of Biochemistry, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
References (90)
90 references, click to expand
  1. Biochemistry and regulation of the protein arginine methyltransferases (PRMTs).
    Arch Biochem Biophys. 2016 Jan 15;590:138-152 PMID: 26612103
  2. A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation.
    Cell. 2015 Aug 27;162(5):1066-77 PMID: 26317470
  3. The biology of lysine acetylation integrates transcriptional programming and metabolism.
    Nutr Metab (Lond). 2011 Mar 03;8:12 PMID: 21371315
  4. Residue-by-Residue View of In Vitro FUS Granules that Bind the C-Terminal Domain of RNA Polymerase II.
    Mol Cell. 2015 Oct 15;60(2):231-41 PMID: 26455390
  5. Citrullination of RGG Motifs in FET Proteins by PAD4 Regulates Protein Aggregation and ALS Susceptibility.
    Cell Rep. 2018 Feb 6;22(6):1473-1483 PMID: 29425503
  6. PhaSepDB: a database of liquid-liquid phase separation related proteins.
    Nucleic Acids Res. 2019 Oct 04;:null PMID: 31584089
  7. Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles.
    Mol Cell. 2015 Mar 5;57(5):936-947 PMID: 25747659
  8. Stress granules as crucibles of ALS pathogenesis.
    J Cell Biol. 2013 Apr 29;201(3):361-72 PMID: 23629963
  9. FLEXITau: Quantifying Post-translational Modifications of Tau Protein in Vitro and in Human Disease.
    Anal Chem. 2016 Apr 5;88(7):3704-14 PMID: 26877193
  10. Acetylation of intrinsically disordered regions regulates phase separation.
    Nat Chem Biol. 2019 Jan;15(1):51-61 PMID: 30531905
  11. A million peptide motifs for the molecular biologist.
    Mol Cell. 2014 Jul 17;55(2):161-9 PMID: 25038412
  12. Bridging biophysics and neurology: aberrant phase transitions in neurodegenerative disease.
    Nat Rev Neurol. 2019 May;15(5):272-286 PMID: 30890779
  13. Global analysis of Cdk1 substrate phosphorylation sites provides insights into evolution.
    Science. 2009 Sep 25;325(5948):1682-6 PMID: 19779198
  14. Liquid demixing of intrinsically disordered proteins is seeded by poly(ADP-ribose).
    Nat Commun. 2015 Aug 19;6:8088 PMID: 26286827
  15. Pi-Pi contacts are an overlooked protein feature relevant to phase separation.
    Elife. 2018 Feb 09;7: PMID: 29424691
  16. Molecular interactions underlying liquid-liquid phase separation of the FUS low-complexity domain.
    Nat Struct Mol Biol. 2019 Jul;26(7):637-648 PMID: 31270472
  17. Phosphorylation by Sky1p promotes Npl3p shuttling and mRNA dissociation.
    RNA. 2001 Feb;7(2):302-13 PMID: 11233987
  18. Regulation of RNA granule dynamics by phosphorylation of serine-rich, intrinsically disordered proteins in C. elegans.
    Elife. 2014 Dec 23;3:e04591 PMID: 25535836
  19. Phosphorylation at Ser8 as an intrinsic regulatory switch to regulate the morphologies and structures of Alzheimer's 40-residue β-amyloid (Aβ40) fibrils.
    J Biol Chem. 2017 May 26;292(21):8846 PMID: 28550132
  20. Membraneless organelles: P granules in Caenorhabditis elegans.
    Traffic. 2019 Jun;20(6):373-379 PMID: 30924287
  21. Tau protein liquid-liquid phase separation can initiate tau aggregation.
    EMBO J. 2018 Apr 3;37(7): PMID: 29472250
  22. The evolutionary scope and neurological disease linkage of yeast-prion-like proteins in humans.
    Biol Direct. 2016 Jul 26;11:32 PMID: 27457357
  23. ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure.
    Cell. 2016 Jan 28;164(3):487-98 PMID: 26777405
  24. Intrinsically Disordered Proteome of Human Membrane-Less Organelles.
    Proteomics. 2018 Mar;18(5-6):e1700193 PMID: 29068531
  25. Neuronal RNA granules: a link between RNA localization and stimulation-dependent translation.
    Neuron. 2001 Nov 20;32(4):683-96 PMID: 11719208
  26. Measles Virus Forms Inclusion Bodies with Properties of Liquid Organelles.
    J Virol. 2019 Oct 15;93(21): PMID: 31375591
  27. Regulation of TDP-43 aggregation by phosphorylation and p62/SQSTM1.
    J Neurochem. 2011 Jan;116(2):248-59 PMID: 21062285
  28. Cellular consequences of arginine methylation.
    Cell Mol Life Sci. 2019 Aug;76(15):2933-2956 PMID: 31101937
  29. Kinase-controlled phase transition of membraneless organelles in mitosis.
    Nature. 2018 Jul;559(7713):211-216 PMID: 29973724
  30. Phosphoproteomic analysis of the mouse brain cytosol reveals a predominance of protein phosphorylation in regions of intrinsic sequence disorder.
    Mol Cell Proteomics. 2008 Jul;7(7):1331-48 PMID: 18388127
  31. RNA-binding proteins with prion-like domains in health and disease.
    Biochem J. 2017 Apr 7;474(8):1417-1438 PMID: 28389532
  32. Sequence and structure-based prediction of eukaryotic protein phosphorylation sites.
    J Mol Biol. 1999 Dec 17;294(5):1351-62 PMID: 10600390
  33. Poly(ADP-ribosyl)ation by PARP1: reaction mechanism and regulatory proteins.
    Nucleic Acids Res. 2019 May 7;47(8):3811-3827 PMID: 30799503
  34. Effect of methylation on the side-chain pKa value of arginine.
    Protein Sci. 2016 Feb;25(2):479-86 PMID: 26540340
  35. Modulation of Intrinsically Disordered Protein Function by Post-translational Modifications.
    J Biol Chem. 2016 Mar 25;291(13):6696-705 PMID: 26851279
  36. RNAs, Phase Separation, and Membrane-Less Organelles: Are Post-Transcriptional Modifications Modulating Organelle Dynamics?
    Bioessays. 2018 Dec;40(12):e1800085 PMID: 30370622
  37. Prion-like domains as epigenetic regulators, scaffolds for subcellular organization, and drivers of neurodegenerative disease.
    Brain Res. 2016 Sep 15;1647:9-18 PMID: 26996412
  38. The function of RNA-binding proteins at the synapse: implications for neurodegeneration.
    Cell Mol Life Sci. 2015 Oct;72(19):3621-35 PMID: 26047658
  39. Liquid phase condensation in cell physiology and disease.
    Science. 2017 Sep 22;357(6357): PMID: 28935776
  40. Global Post-Translational Modification Discovery.
    J Proteome Res. 2017 Apr 7;16(4):1383-1390 PMID: 28248113
  41. m6A enhances the phase separation potential of mRNA.
    Nature. 2019 Jul;571(7765):424-428 PMID: 31292544
  42. Prion-like Domains in Eukaryotic Viruses.
    Sci Rep. 2018 Jun 12;8(1):8931 PMID: 29895872
  43. Intrinsically disordered proteins in overcrowded milieu: Membrane-less organelles, phase separation, and intrinsic disorder.
    Curr Opin Struct Biol. 2017 Jun;44:18-30 PMID: 27838525
  44. RNA-associated protein 55 (RAP55) localizes to mRNA processing bodies and stress granules.
    RNA. 2006 Apr;12(4):547-54 PMID: 16484376
  45. Protein interfaces in signaling regulated by arginine methylation.
    Sci STKE. 2005 Feb 15;2005(271):re2 PMID: 15713950
  46. Phosphoregulated FMRP phase separation models activity-dependent translation through bidirectional control of mRNA granule formation.
    Proc Natl Acad Sci U S A. 2019 Mar 5;116(10):4218-4227 PMID: 30765518
  47. Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization.
    Cell. 2015 Sep 24;163(1):123-33 PMID: 26406374
  48. Physiological, Pathological, and Targetable Membraneless Organelles in Neurons.
    Trends Neurosci. 2019 Oct;42(10):693-708 PMID: 31493925
  49. The Biological Axis of Protein Arginine Methylation and Asymmetric Dimethylarginine.
    Int J Mol Sci. 2019 Jul 06;20(13):null PMID: 31284549
  50. Sequence Determinants of Intracellular Phase Separation by Complex Coacervation of a Disordered Protein.
    Mol Cell. 2016 Jul 7;63(1):72-85 PMID: 27392146
  51. FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions.
    Cell. 2018 Apr 19;173(3):720-734.e15 PMID: 29677515
  52. The importance of intrinsic disorder for protein phosphorylation.
    Nucleic Acids Res. 2004 Feb 11;32(3):1037-49 PMID: 14960716
  53. Lysine/RNA-interactions drive and regulate biomolecular condensation.
    Nat Commun. 2019 Jul 2;10(1):2909 PMID: 31266957
  54. Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity.
    EMBO J. 2017 Oct 16;36(20):2951-2967 PMID: 28790177
  55. Droplet organelles?
    EMBO J. 2016 Aug 1;35(15):1603-12 PMID: 27357569
  56. Liquid-liquid phase separation in biology.
    Annu Rev Cell Dev Biol. 2014;30:39-58 PMID: 25288112
  57. A Molecular Grammar Governing the Driving Forces for Phase Separation of Prion-like RNA Binding Proteins.
    Cell. 2018 Jul 26;174(3):688-699.e16 PMID: 29961577
  58. Phase Separation of FUS Is Suppressed by Its Nuclear Import Receptor and Arginine Methylation.
    Cell. 2018 Apr 19;173(3):706-719.e13 PMID: 29677514
  59. Tau paired helical filaments from Alzheimer's disease brain and assembled in vitro are based on beta-structure in the core domain.
    Biochemistry. 2004 Feb 17;43(6):1694-703 PMID: 14769047
  60. Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics.
    Mol Cell. 2017 Mar 16;65(6):1044-1055.e5 PMID: 28306503
  61. Mechanistic View of hnRNPA2 Low-Complexity Domain Structure, Interactions, and Phase Separation Altered by Mutation and Arginine Methylation.
    Mol Cell. 2018 Feb 1;69(3):465-479.e7 PMID: 29358076
  62. Amyloid polymorphism: structural basis and neurobiological relevance.
    Neuron. 2015 May 6;86(3):632-45 PMID: 25950632
  63. The prionlike domain of FUS is multiphosphorylated following DNA damage without altering nuclear localization.
    Mol Biol Cell. 2018 Aug 1;29(15):1786-1797 PMID: 29897835
  64. PARylation regulates stress granule dynamics, phase separation, and neurotoxicity of disease-related RNA-binding proteins.
    Cell Res. 2019 Mar;29(3):233-247 PMID: 30728452
  65. Liquid-liquid phase separation of tau protein: The crucial role of electrostatic interactions.
    J Biol Chem. 2019 Jul 19;294(29):11054-11059 PMID: 31097543
  66. Phase Separation: Linking Cellular Compartmentalization to Disease.
    Trends Cell Biol. 2016 Jul;26(7):547-558 PMID: 27051975
  67. The P Granules of C. elegans: A Genetic Model for the Study of RNA-Protein Condensates.
    J Mol Biol. 2018 Nov 2;430(23):4702-4710 PMID: 30096346
  68. The prion-like protein kinase Sky1 is required for efficient stress granule disassembly.
    Nat Commun. 2019 Aug 9;10(1):3614 PMID: 31399582
  69. Amyotrophic lateral sclerosis-linked mutations increase the viscosity of liquid-like TDP-43 RNP granules in neurons.
    Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):E2466-E2475 PMID: 28265061
  70. The C-Terminal RGG Domain of Human Lsm4 Promotes Processing Body Formation Stimulated by Arginine Dimethylation.
    Mol Cell Biol. 2016 Aug 12;36(17):2226-35 PMID: 27247266
  71. Internalized Tau sensitizes cells to stress by promoting formation and stability of stress granules.
    Sci Rep. 2016 Jul 27;6:30498 PMID: 27460788
  72. Acetylation Disfavors Tau Phase Separation.
    Int J Mol Sci. 2018 May 04;19(5):null PMID: 29734651
  73. Chemical biology of protein arginine modifications in epigenetic regulation.
    Chem Rev. 2015 Jun 10;115(11):5413-61 PMID: 25970731
  74. Structural insights into functional and pathological amyloid.
    J Biol Chem. 2011 May 13;286(19):16533-40 PMID: 21454545
  75. The Role of Post-Translational Modifications on Prion-Like Aggregation and Liquid-Phase Separation of FUS.
    Int J Mol Sci. 2018 Mar 16;19(3):null PMID: 29547565
  76. Defining the RGG/RG motif.
    Mol Cell. 2013 Jun 6;50(5):613-23 PMID: 23746349
  77. Dual specificity kinase DYRK3 couples stress granule condensation/dissolution to mTORC1 signaling.
    Cell. 2013 Feb 14;152(4):791-805 PMID: 23415227
  78. Classification of intrinsically disordered regions and proteins.
    Chem Rev. 2014 Jul 9;114(13):6589-631 PMID: 24773235
  79. Peptidylarginine deiminase 4 and citrullination in health and disease.
    Autoimmun Rev. 2010 Jan;9(3):158-60 PMID: 19540364
  80. A single N-terminal phosphomimic disrupts TDP-43 polymerization, phase separation, and RNA splicing.
    EMBO J. 2018 Mar 1;37(5): PMID: 29438978
  81. The world of protein acetylation.
    Biochim Biophys Acta. 2016 Oct;1864(10):1372-401 PMID: 27296530
  82. Friend or foe-Post-translational modifications as regulators of phase separation and RNP granule dynamics.
    J Biol Chem. 2019 May 3;294(18):7137-7150 PMID: 30587571
  83. Intrinsically disordered sequences enable modulation of protein phase separation through distributed tyrosine motifs.
    J Biol Chem. 2017 Nov 17;292(46):19110-19120 PMID: 28924037
  84. Mitochondrial RNA Granules Are Centers for Posttranscriptional RNA Processing and Ribosome Biogenesis.
    Cell Rep. 2015 Feb 17;10(6):920-932 PMID: 25683715
  85. Expanding the proteome: disordered and alternatively folded proteins.
    Q Rev Biophys. 2011 Nov;44(4):467-518 PMID: 21729349
  86. PRMT1 is required for RAP55 to localize to processing bodies.
    RNA Biol. 2012 May;9(5):610-23 PMID: 22614839
  87. Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies.
    Acta Neuropathol. 2009 Feb;117(2):137-49 PMID: 19125255
  88. Poly(ADP-ribose) regulates stress responses and microRNA activity in the cytoplasm.
    Mol Cell. 2011 May 20;42(4):489-99 PMID: 21596313
  89. Poly(ADP-Ribose) Prevents Pathological Phase Separation of TDP-43 by Promoting Liquid Demixing and Stress Granule Localization.
    Mol Cell. 2018 Sep 6;71(5):703-717.e9 PMID: 30100264
  90. Inhibition of Axon Regeneration by Liquid-like TIAR-2 Granules.
    Neuron. 2019 Oct 23;104(2):290-304.e8 PMID: 31378567
Article Info
Journal
International journal of molecular sciences
Abbr.
Int J Mol Sci
ISSN
1422-0067
DOI
10.3390/ijms20215501
Published
2019-11-05
Epub
2019-00-05
Language
English
Region
Switzerland
NLM ID
101092791
PMCID
PMC6861982
Subset
IM
Grants
NIGMS NIH HHS · R35 GM119790 · United States
NIGMS NIH HHS · R35GM119790 · United States
External Links
PubMed source DOI: 10.3390/ijms20215501 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2