Intrinsically disordered proteins in cellular signalling and regulation

Nature Reviews Molecular Cell Biology

Volumn 16, Issue 1, 2015, Pages 18-29

  Wright, Peter E ^a   Dyson, H Jane ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

INTRINSICALLY DISORDERED PROTEIN; RNA POLYMERASE; MULTIPROTEIN COMPLEX;

ALLOSTERISM; ALTERNATIVE RNA SPLICING; BIOINFORMATICS; HUMAN; INTRACELLULAR SIGNALING; MACHINE; MOLECULAR CLOCK; NEGATIVE FEEDBACK; PRIORITY JOURNAL; PROTEIN FOLDING; PROTEIN MODIFICATION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; REGULATORY MECHANISM; REVIEW; RNA SPLICING; TISSUE SPECIFICITY; ANIMAL; ANTIBODY SPECIFICITY; GENETICS; METABOLISM; PHYSIOLOGY; PROTEIN PROCESSING; SIGNAL TRANSDUCTION;

ALTERNATIVE SPLICING; ANIMALS; HUMANS; INTRINSICALLY DISORDERED PROTEINS; MULTIPROTEIN COMPLEXES; ORGAN SPECIFICITY; PROTEIN PROCESSING, POST-TRANSLATIONAL; SIGNAL TRANSDUCTION;

EID: 84925114160     PISSN: 14710072     EISSN: 14710080     Source Type: Journal    
DOI: 10.1038/nrm3920     Document Type: Review

References (146)

1. Wright, P. E. & Dyson, H. J. Intrinsically unstructured proteins: re assessing the protein structure-function paradigm. J. Mol. Biol. 293, 321-331 (1999
2. Dunker, A. K., Brown, C. J., Lawson, J. D., Iakoucheva, L. M. & Obradovic, Z. Intrinsic disorder and protein function. Biochemistry 41, 6573-6582 (2002
3. Dyson, H. J. & Wright, P. E. Intrinsically unstructured proteins and their functions. Nature Rev. Mol. Cell Biol. 6, 197-208 (2005
4. van der Lee, R., et al. Classification of intrinsically disordered regions and proteins. Chem. Rev. 114, 6589-6631 (2014
5. Dunker, A. K., Cortese, M. S., Romero, P., Iakoucheva, L. M. & Uversky, V. N. Flexible nets. The roles of intrinsic disorder in protein interaction networks. FEBS J. 272, 5129-5148 (2005
6. Kim, P. M., Sboner, A., Xia, Y. & Gerstein, M. The role of disorder in interaction networks: a structural analysis. Mol. Systems Biol. 4, 179 (2008
7. Iakoucheva, L. M., Brown, C. J., Lawson, J. D., Obradovic, Z. & Dunker, A. K. Intrinsic disorder in cell-signaling and cancer-Associated proteins. J. Mol. Biol. 323, 573-584 (2002
8. Liu, J., et al. Intrinsic disorder in transcription factors. Biochemistry 45, 6873-6888 (2006
9. Galea, C. A., Wang, Y., Sivakolundu, S. G. & Kriwacki, R. W. Regulation of cell division by intrinsically unstructured proteins: intrinsic flexibility, modularity, and signaling conduits. Biochemistry 47, 7598-7609 (2008
10. Gsponer, J., Futschik, M. E., Teichmann, S. A. & Babu, M. M. Tight regulation of unstructured proteins: from transcript synthesis to protein degradation. Science 322, 1365-1368 (2008
11. Vavouri, T., Semple, J. I., Garcia-Verdugo, R. & Lehner, B. Intrinsic protein disorder and interaction promiscuity are widely associated with dosage sensitivity. Cell 138, 198-208 (2009
12. Babu, M. M., van der Lee, R., de Groot, N. S. & Gsponer, J. Intrinsically disordered proteins: regulation and disease. Curr. Opin. Struct. Biol. 21, 432-440 (2011
13. Tompa, P. The interplay between structure and function in intrinsically unstructured proteins. FEBS Lett. 579, 3346-3354 (2005
14. Frey, S., Richter, R. P. & Görlich, D. FG rich repeats of nuclear pore proteins form a three-dimensional meshwork with hydrogel-like properties. Science 314, 815-817 (2006
15. Tompa, P. Structure and Function of Intrinsically Disordered Proteins (Chapman & Hall/CRC, 2009
16. Guharoy, M., Szabo, B., Martos, S. C., Kosol, S. & Tompa, P. Intrinsic structural disorder in cytoskeletal proteins. Cytoskeleton 70, 550-571 (2013
17. Kato, M., et al. Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell 149, 753-767 (2012
18. Weber, S. C. & Brangwynne, C. P. Getting RNA and protein in phase. Cell 149, 1188-1191 (2012
19. Oldfield, C. J., et al. Coupled folding and binding with a helix-forming molecular recognition elements. Biochemistry 44, 12454-12470 (2005
20. Pontius, B. W. Close encounters: why unstructured, polymeric domains can increase rates of specific macromolecular association. Trends Biochem. Sci. 18, 181-186 (1993
21. Stein, A., Pache, R. A., Bernadó, P., Pons, M. & Aloy, P. Dynamic interactions of proteins in complex networks: a more structured view. FEBS J. 276, 5390-5405 (2009
22. Gsponer, J. & Babu, M. M. The rules of disorder or why disorder rules. Progress Biophys. Mol. Biol. 99, 94-103 (2009
23. Lee, C. W., Ferreon, J. C., Ferreon, A. C., Arai, M. & Wright, P. E. Graded enhancement of p53 binding to CREB-binding protein (CBP) by multisite phosphorylation. Proc. Natl Acad. Sci. USA 107, 19290-19295 (2010
24. Borg, M., et al. Polyelectrostatic interactions of disordered ligands suggest a physical basis for ultrasensitivity. Proc. Natl Acad. Sci. USA 104, 9650-9655 (2007
25. Van Roey, K., Dinkel, H., Weatheritt, R. J., Gibson, T. J. & Davey, N. E. The switches. ELM resource: a compendium of conditional regulatory interaction interfaces. Sci. Signal. 6, rs7 (2013
26. Van Roey, K., Gibson, T. J. & Davey, N. E. Motif switches: decision-making in cell regulation. Curr. Opin. Struct. Biol. 22, 378-385 (2012
27. Oates, M. E., et al. D2P2: database of disordered protein predictions. Nucleic Acids Res. 41, D508-D516 (2013
28. Marsh, J. A. & Forman-Kay, J. D. Ensemble modeling of protein disordered states: experimental restraint contributions and validation. Proteins 80, 556-572 (2012
29. Salmon, L., et al. NMR characterization of long-range order in intrinsically disordered proteins. J. Am. Chem. Soc. 132, 8407-8418 (2010
30. Sibille, N. & Bernadó, P. Structural characterization of intrinsically disordered proteins by the combined use of NMR and SAXS. Biochem. Soc. Trans. 40, 955-962 (2012
31. Varadi, M., et al. pE DB: a database of structural ensembles of intrinsically disordered and of unfolded proteins. Nucleic Acids Res. 42, D326-D335 (2014
32. Ferreon, A. C., Moran, C. R., Gambin, Y. & Deniz, A. A. Single-molecule fluorescence studies of intrinsically disordered proteins. Methods Enzymol. 472, 179-204 (2010
33. Hofmann, H., et al. Polymer scaling laws of unfolded and intrinsically disordered proteins quantified with single-molecule spectroscopy. Proc. Natl Acad. Sci. USA 109, 16155-16160 (2012
34. Das, R. K. & Pappu, R. V. Conformations of intrinsically disordered proteins are influenced by linear sequence distributions of oppositely charged residues. Proc. Natl Acad. Sci. USA 110, 13392-13397 (2013
35. Dyson, H. J. & Wright, P. E. Coupling of folding and binding for unstructured proteins. Curr. Opin. Struct. Biol. 12, 54-60 (2002
36. Mohan, A., et al. Analysis of molecular recognition features (MoRFs). J. Mol. Biol. 362, 1043-1059 (2006
37. Neduva, V. & Russell, R. B. Linear motifs: Evolutionary interaction switches. FEBS Lett. 579, 3342-3345 (2005
38. Tompa, P., Davey, N. E., Gibson, T. J. & Babu, M. M. A million peptide motifs for the molecular biologist. Mol. Cell 55, 161-169 (2014
39. Demarest, S. J., et al. Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators. Nature 415, 549-553 (2002
40. Waters, L., et al. Structural diversity in p160/CREB-binding protein coactivator complexes. J. Biol. Chem. 281, 14787-14795 (2006
41. Qin, B. Y., et al. Crystal Structure of IRF 3 in complex with CBP. Structure 13, 1269-1277 (2005
42. Spolar, R. S. & Record, M. T. Coupling of local folding to site-specific binding of proteins to DNA. Science 263, 777-784 (1994
43. Fuxreiter, M., Simon, I., Friedrich, P. & Tompa, P. Preformed structural elements feature in partner recognition by intrinsically unstructured proteins. J. Mol. Biol. 338, 1015-1026 (2004
44. Sugase, K., Dyson, H. J. & Wright, P. E. Mechanism of coupled folding and binding of an intrinsically disordered protein. Nature 447, 1021-1025 (2007
45. Shammas, S., Travis, A. J. & Clarke, J. Remarkably fast coupled folding and binding of the intrinsically disordered transactivation domain of cMyb to CBP KIX. J. Phys. Chem. B 117, 13346-13356 (2013
46. Gianni, S., Morrone, A., Giri, R. & Brunori, M. A folding-After-binding mechanism describes the recognition between the transactivation domain of c Myb and the KIX domain of the CREB-binding protein. Biochem. Biophys. Res. Commun. 428, 205-209 (2012
47. Shammas, S. L., Travis, A. J. & Clarke, J. Allostery within a transcription coactivator is predominantly mediated through dissociation rate constants. Proc. Natl Acad. Sci. USA 111, 12049-12054 (2014
48. Rogers, J. M., Wong, C. T. & Clarke, J. Coupled folding and binding of the disordered protein PUMA does not require particular residual structure. J. Am. Chem. Soc. 136, 5197-5200 (2014
49. Dogan, J., Schmidt, T., Mu, X., Engström, Å. & Jemth, P. Fast association and slow transitions in the interaction between two intrinsically disordered protein domains. J. Biol. Chem. 287, 34316-34324 (2012
50. Iešmantavic?ius, V., Dogan, J., Jemth, P., Teilum, K. & Kjaergaard, M. Helical propensity in an intrinsically disordered protein accelerates ligand binding. Angew. Chem. Int. Ed. Engl. (2014
51. Schafmeister, C. E., Po, J. & Verdine, G. L. An all-hydrocarbon cross-linking system for enhancing the helicity and metabolic stability of peptides. J. Am. Chem. Soc. 122, 5891-5892 (2000
52. Bienkiewicz, E A., Adkins, J. N. & Lumb, K. J. Functional consequences of preorganized helical structure in the intrinsically disordered cell-cycle inhibitor p27Kip1. Biochemistry 41, 752-759 (2002
53. Baek, S., et al. Structure of the stapled p53 peptide bound to Mdm2. J. Am. Chem. Soc. 134, 103-106 (2011
54. Otieno, S. & Kriwacki, R. Probing the role of nascent helicity in p27 function as a cell cycle regulator. PLoS ONE 7, e47177 (2012
55. Borcherds, W., et al. Disorder and residual helicity alter p53 Mdm2 binding affinity and signaling in cells. Nature Chem. Biol. 10, 1000-1002 (2014
56. Bertagna, A., Toptygin, D., Brand, L. & Barrick, D. The effects of conformational heterogeneity on the binding of the Notch intracellular domain to effector proteins: a case of biologically tuned disorder. Biochem. Soc. Trans. 36, 157-166 (2008
57. Wang, Y., et al. Intrinsic disorder mediates the diverse regulatory functions of the Cdk inhibitor p21. Nature Chem. Biol. 7, 214-221 (2011
58. Baker, J. M. R., et al. CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices. Nature Struct. Mol. Biol. 14, 738-745 (2007
59. Mittag, T., et al. Structure/function implications in a dynamic complex of the intrinsically disordered Sic1 with the Cdc4 subunit of an SCF ubiquitin ligase. Structure 18, 494-506 (2010
60. Tompa, P. & Fuxreiter, M. Fuzzy complexes: polymorphism and structural disorder in protein-protein interactions. Trends Biochem. Sci. 33, 2-8 (2008
61. Ferreon, J. C., Martinez-Yamout, M. A., Dyson, H. J. & Wright, P. E. Structural basis for subversion of cellular control mechanisms by the adenoviral E1A oncoprotein. Proc. Natl Acad. Sci. USA 106, 13260-13265 (2009
62. Ishiyama, N., et al. Dynamic and static interactions between p120 catenin and E cadherin regulate the stability of cell-cell adhesion. Cell 141, 117-128 (2010
63. Ferreon, A. C., Ferreon, J. C., Wright, P. E. & Deniz, A. A. Modulation of allostery by protein intrinsic disorder. Nature 498, 390-394 (2013
64. Flock, T., Weatheritt, R. J., Latysheva, N. S. & Babu, M. M. Controlling entropy to tune the functions of intrinsically disordered regions. Curr. Opin. Struct. Biol. 26, 62-72 (2014
65. Mukherjee, S. P., et al. Analysis of the RelA:CBP/p300 interaction reveals its involvement in NF κ B-driven transcription. PLoS Biol. 11, e1001647 (2013
66. Pelka, P., Ablack, J. N. G., Fonseca, G. J., Yousef, A. F. & Mymryk, J. S. Intrinsic structural disorder in adenovirus E1A: a viral molecular hub linking multiple diverse processes. J. Virol. 82, 7252-7263 (2008
67. Berk, A. J. Recent lessons in gene expression, cell cycle control, and cell biology from adenovirus. Oncogene 24, 7673-7685 (2005
68. Fax, P., Lipinski, K. S., Esche, H. & Brockmann, D. cAMP-independent activation of the adenovirus type 12 E2 promoter correlates with the recruitment of CREB 1/ATF 1, E1A12S, and CBP to the E2 CRE. J. Biol. Chem. 275, 8911-8920 (2000
69. Green, M., Panesar, N. K. & Loewenstein, P. M. The transcription-repression domain of the adenovirus E1A oncoprotein targets p300 at the promoter. Oncogene 27, 4446-4455 (2008
70. Frye, J. J., et al. Electron microscopy structure of human APC/CCDH1-EMI1 reveals multimodal mechanism of E3 ligase shutdown. Nature Struct. Mol. Biol. 20, 827-835 (2013
71. Nussinov, R. & Tsai, C. J. Allostery in disease and in drug discovery. Cell 153, 293-305 (2013
72. Motlagh, H. N., Wrabl, J. O., Li, J. & Hilser, V. J. The ensemble nature of allostery. Nature 508, 331-339 (2014
73. Hilser, V. J. & Thompson, E. B. Intrinsic disorder as a mechanism to optimize allosteric coupling in proteins. Proc. Natl Acad. Sci. USA 104, 8311-8315 (2007
74. Garcia-Pino, A., et al. Allostery and intrinsic disorder mediate transcription regulation by conditional cooperativity. Cell 142, 101-111 (2010
75. Li, J., Motlagh, H. N., Chakuroff, C., Thompson, E. B. & Hilser, V. J. Thermodynamic dissection of the intrinsically disordered N terminal domain of human glucocorticoid receptor. J. Biol. Chem. 287, 26777-26787 (2012
76. Krishnan, N., et al. Targeting the disordered C terminus of PTP1B with an allosteric inhibitor. Nature Chem. Biol. 10, 558-566 (2014
77. Pejaver, V., et al. The structural and functional signatures of proteins that undergo multiple events of post-Translational modification. Protein Sci. 23, 1077-1093 (2014
78. Iakoucheva, L. M., et al. The importance of intrinsic disorder for protein phosphorylation. Nucleic Acids Res. 32, 1037-1049 (2004
79. Chrivia, J. C., et al. Phosphorylated CREB binds specifically to nuclear protein CBP. Nature 365, 855-859 (1993
80. Radhakrishnan, I., et al. Solution structure of the KIX domain of CBP bound to the transactivation domain of CREB: A model for activator:coactivator interactions. Cell 91, 741-752 (1997
81. Nash, P., et al. Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication. Nature 414, 514-521 (2001
82. Mittag, T., et al. Dynamic equilibrium engagement of a polyvalent ligand with a single-site receptor. Proc. Natl Acad. Sci. USA 105, 17772-17777 (2008
83. Samaga, R. & Klamt, S. Modeling approaches for qualitative and semi-quantitative analysis of cellular signaling networks. Cell Commun. Signal. 11, 43 (2013
84. Ferrell, J. E. Jr & Ha, S. H. Ultrasensitivity part II: multisite phosphorylation, stoichiometric inhibitors, and positive feedback. Trends Biochem. Sci. 39, 556-569 (2014
85. Lyons, N. A., Fonslow, B. R., Diedrich, J. K., Yates, J. R. & Morgan, D. O. Sequential primed kinases create a damage-responsive phosphodegron on Eco1. Nature Struct. Mol. Biol. 20, 194-201 (2013
86. Meek, D. W. & Anderson, C. W. Posttranslational Modification of p53: Cooperative integrators of function. Cold Spring Harb. Perspect. Biol. 1, a000950 (2009
87. Kruse, J. P. & Gu, W. Modes of p53 regulation. Cell 137, 609-622 (2009
88. Vousden, K H. & Prives, C. Blinded by the light: The growing complexity of p53. Cell 137, 413-431 (2009
89. Grossman, S R., et al. Polyubiquitination of p53 by a ubiquitin ligase activity of p300. Science 300, 342 (2003
90. Ferreon, J. C., et al. Cooperative regulation of p53 by modulation of ternary complex formation with CBP/p300 and HDM2. Proc. Natl Acad. Sci. USA 106, 6591-6596 (2009
91. Sakaguchi, K., et al. Damage-mediated phosphorylation of human p53 threonine 18 through a cascade mediated by a casein 1 like kinase. Effect on Mdm2 binding. J. Biol. Chem. 275, 9278-9283 (2000
92. Schon, O., Friedler, A., Freund, S. & Fersht, A. R. Binding of p53 derived ligands to MDM2 induces a variety of long range conformational changes. J. Mol. Biol. 336, 197-202 (2004
93. Müller-Späth, S., et al. Charge interactions can dominate the dimensions of intrinsically disordered proteins. Proc. Natl Acad. Sci. USA 107, 14609-14614 (2010
94. Querfurth, C., et al. Circadian conformational change of the Neurospora clock protein FREQUENCY triggered by clustered hyperphosphorylation of a basic domain. Mol. Cell 43, 713-722 (2011
95. Baker, C. L., Kettenbach, A. N., Loros, J. J., Gerber, S. A. & Dunlap, J. C. Quantitative proteomics reveals a dynamic interactome and phase-specific phosphorylation in the Neurospora circadian clock. Mol. Cell 34, 354-363 (2009
96. Tang, C. T., et al. Setting the pace of the Neurospora circadian clock by multiple independent FRQ phosphorylation events. Proc. Natl Acad. Sci. USA 106, 10722-10727 (2009
97. Holt, L. J., et al. Global analysis of Cdk1 substrate phosphorylation sites provides insights into evolution. Science 325, 1682-1686 (2009
98. Kõivomägi, M., et al. Multisite phosphorylation networks as signal processors for Cdk1. Nature Struct. Mol. Biol. 20, 1415-1424 (2013
99. Pufall, M. A. & Graves, B. J. Autoinhibitory domains: modular effectors of cellular regulation. Annu. Rev. Cell Dev. Biol. 18, 421-462 (2002
100. Trudeau, T., et al. Structure and intrinsic disorder in protein autoinhibition. Structure 21, 332-341 (2013
101. Li, P., Martins, I. R. S., Amarasinghe, G. K. & Rosen, M. K. Internal dynamics control activation and activity of the autoinhibited Vav DH domain. Nature Struct. Mol. Biol. 15, 613-618 (2008
102. Yu, B., et al Structural and energetic mechanisms of cooperative autoinhibition and activation of Vav1. Cell 140, 246-256 (2010
103. Wu, H. Higher-order assemblies in a new paradigm of signal transduction. Cell 153, 287-292 (2013
104. Weatheritt, R. J., Gibson, T. J. & Babu, M. M. Asymmetric mRNA localization contributes to fidelity and sensitivity of spatially localized systems. Nature Struct. Mol. Biol. 21, 833-839 (2014
105. Li, J., et al. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 150, 339-350 (2012
106. Li, P., et al. Phase transitions in the assembly of multivalent signalling proteins. Nature 483, 336-340 (2012
107. Kedersha, N., Ivanov, P. & Anderson, P. Stress granules and cell signaling: more than just a passing phase?. Trends Biochem. Sci. 38, 494-506 (2013
108. Wippich, F., et al. Dual specificity kinase DYRK3 couples stress granule condensation/dissolution to mTORC1 signaling. Cell 152, 791-805 (2013
109. Michelitsch, M. D. & Weissman, J. S. A census of glutamine/asparagine-rich regions: Implications for their conserved function and the prediction of novel prions. Proc. Natl Acad. Sci. USA 97, 11910-11915 (2000
110. Wang, E. T., et al. Alternative isoform regulation in human tissue transcriptomes. Nature 456, 470-476 (2008
111. Buljan, M., et al. Tissue-specific splicing of disordered segments that embed binding motifs rewires protein interaction networks. Mol. Cell 46, 871-883 (2012
112. Ellis, J. D., et al. Tissue-specific alternative splicing remodels protein-protein interaction networks. Mol. Cell 46, 884-892 (2012
113. Korneta, I. & Bujnicki, J. M. Intrinsic disorder in the human spliceosomal proteome. PLoS Computat. Biol. 8, e1002641 (2012
114. Romero, P. R., et al. Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms. Proc. Natl Acad. Sci. USA 103, 8390-8395 (2006
115. Mermoud, J. E., Cohen, P. & Lamond, A. I. Ser/Thr-specific protein phosphatases are required for both catalytic steps of pre-mRNA splicing. Nucleic Acids Res. 20, 5263-5269 (1992
116. Xiao, S. H. & Manley, J. L. Phosphorylation of the ASF/SF2 RS domain affects both protein-protein and protein-RNA interactions and is necessary for splicing. Genes Dev. 11, 334-344 (1997
117. Xiang, S., et al. Phosphorylation drives a dynamic switch in serine/arginine-rich proteins. Structure 21, 2162-2174 (2013
118. Kwon, I., et al. Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science 345, 1139-1145 (2014
119. Muñoz, M. J., de la Mata, M. & Kornblihtt, A. R. The carboxy terminal domain of RNA polymerase II and alternative splicing. Trends Biochem. Sci. 35, 497-504 (2010
120. Hsin, J. P. & Manley, J. L. The RNA polymerase II CTD coordinates transcription and RNA processing. Genes Dev. 26, 2119-2137 (2012
121. David, C. J., Boyne, A. R., Millhouse, S. R. & Manley, J. L. The RNA polymerase II C terminal domain promotes splicing activation through recruitment of a U2AF65-Prp19 complex. Genes Dev. 25, 972-983 (2011
122. Dye, M. J., Gromak, N. & Proudfoot, N. J. Exon tethering in transcription by RNA polymerase II. Mol. Cell 21, 849-859 (2006
123. Theillet, F. X., et al. Physicochemical properties of cells and their effects on intrinsically disordered proteins (IDPs). Chem. Rev. 114, 6661-6714 (2014
124. Sakon, J. J. & Weninger, K. R. Detecting the conformation of individual proteins in live cells. Nature Methods 7, 203-205 (2010
125. Gebhardt, J. C., et al. Single-molecule imaging of transcription factor binding to DNA in live mammalian cells. Nature Methods 10, 421-426 (2013
126. Wells, M., et al. Structure of tumor suppressor p53 and its intrinsically disordered N terminal transactivation domain. Proc. Natl Acad. Sci. USA 105, 5762-5767 (2008
127. Cheng, Y., et al. Rational drug design via intrinsically disordered protein. Trends Biotechnol. 24, 435-442 (2006
128. Mészáros, B., Tompa, P., Simon, I. & Dosztányi, Z. Molecular principles of the interactions of disordered proteins. J. Mol. Biol. 372, 549-561 (2007
129. Lao, B. B., et al. Rational design of topographical helix mimics as potent inhibitors of protein-protein interactions. J. Am. Chem. Soc. 136, 7877-7888 (2014
130. Lao, B. B., et al. In vivo modulation of hypoxia-inducible signaling by topographical helix mimetics. Proc. Natl Acad. Sci. USA 111, 7588-7593 (2014
131. Hammoudeh, D. I., Follis, A. V., Prochownik, E. V. & Metallo, S. J. Multiple independent binding sites for small-molecule inhibitors on the oncoprotein c myc. J. Am. Chem. Soc. 131, 7390-7401 (2009
132. Davey, N. E., Trave, G. & Gibson, T. J. How viruses hijack cell regulation. Trends Biochem. Sci. 36, 159-169 (2011
133. Hagai, T., Azia, A., Babu, M. M. & Andino, R. Use of host-like peptide motifs in viral proteins is a prevalent strategy in host-virus interactions. Cell Rep. 7, 1729-1739 (2014
134. Peng, K., et al. Optimizing intrinsic disorder predictors with protein evolutionary information. J. Bioinform. Comput. Biol. 3, 35-60 (2005
135. Dosztányi, Z., Csizmok, V., Tompa, P. & Simon, I. The pairwise energy content estimated from amino acid composition discriminates between folded and intrinsically unstructured proteins. J. Mol. Biol. 347, 827-839 (2005
136. Dosztányi, Z., Csizmok, V., Tompa, P. & Simon, I. IUPred: web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content. Bioinformatics 21, 3433-3434 (2005
137. Dosztányi, Z., Mészáros, B. & Simon, I. ANCHOR: web server for predicting protein binding regions in disordered proteins. Bioinformatics 25, 2745-2746 (2009
138. Mészáros, B., Simon, I. & Dosztányi, Z. Prediction of protein binding regions in disordered proteins. PLoS Comput. Biol. 5, e1000376 (2009
139. Obradovic, Z., et al. Predicting intrinsic disorder from amino acid sequence. Proteins: Struct. Function Bioinformat. 53 (Suppl. 6), 566-572 (2003
140. Ishida, T. & Kinoshita, K. PrDOS: prediction of disordered protein regions from amino acid sequence. Nucleic Acids Res. 35, W460-W464 (2007
141. Walsh, I., Martin, A. J., Di Domenico, T. & Tosatto, S. C. ESpritz: accurate and fast prediction of protein disorder. Bioinformatics 28, 503-509 (2012
142. Fukuchi, S., Homma, K., Minezaki, Y., Gojobori, T. & Nishikawa, K. Development of an accurate classification system of proteins into structured and unstructured regions that uncovers novel structural domains: its application to human transcription factors. BMC Struct. Biol. 9, 26 (2009
143. Wojciak, J. M., Martinez-Yamout, M. A., Dyson, H. J. & Wright, P. E. Structural basis for recruitment of CBP/p300 coactivators by STAT1 and STAT2 transactivation domains. EMBO J. 28, 948-958 (2009
144. Bösch, C., Bundi, A., Oppliger, M. & Wüthrich, K. 1H nuclear-magnetic-resonance studies of the molecular conformation of monomeric glucagon in aqueous solution. Eur. J. Biochem. 91, 209-214 (1978
145. Altarejos, J. Y. & Montminy, M. CREB and the CRTC co activators: sensors for hormonal and metabolic signals. Nature Rev. Mol. Cell Biol. 12, 141-151 (2011
146. Sickmeier, M., et al. DisProt: the database of disordered proteins. Nucleic Acids Res. 35, D786-D793 (2007