Allosteric Modulation of Intrinsically Disordered Proteins

  • Ashfaq Ur Rehman
  • Mueed Ur Rahman
  • Taaha Arshad
  • Hai-Feng ChenEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1163)


The allosteric property of globular proteins is applauded as their intrinsic ability to regulate distant sites, and this property further plays a critical role in a wide variety of cellular regulatory mechanisms. Recent advancements and studies have revealed the manifestation of allostery in intrinsically disordered proteins or regions as allosteric sites present within or mediated by IDP/IDRs facilitates the signaling interactions for various biological mechanisms which would otherwise be impossible for globular proteins to regulate. This thematic review has highlighted the biological outcomes that can be achieved by the mechanism of allosteric regulation of intrinsically disordered proteins or regions. The similar mechanism has been implemented on Adenovirus 5 early region 1A and tumor apoptosis protein p53 in correspondence with other partners in binary and ternary complexes, which are the subject of the current review. Both these proteins regulate once they bind to their partners, consequently, forming either a binary or a ternary complex. Allosteric regulation by IDPs is currently a subject undergoing intense study, and the ongoing research work will ensure a better understanding of precision and efficiency of cellular regulation by them. Allosteric regulation mechanism can also be researched by intrinsically disordered protein-specific force field.


Allosteric regulation IDPs E1A p53 Partners 



Ataxia-telangiectasia mutated (gene ATM)


Ataxia-telangiectasia and Rad3-related (ATR)


CDK-activating kinase


CREB-binding protein (CREBBP)


Cell division cycle 2 kinase


Cyclin-dependent kinases (multiple members)


Cell cycle checkpoint kinase 1 (CHEK1)


Cell cycle checkpoint kinase 2 (CHEK2)


Casein kinase 1 (multiple isoforms)


Casein kinase 2 (multiple isoforms)


COP9 signalosome (protein complex)


DNA-dependent protein kinase (PRKDC)


p42 mitogen-activated protein kinase (MAPK1)


Facilitating chromatin-mediated transcription


Homeodomain-interacting protein kinase 2


Jun N-terminal kinase (MAPK8)


Mouse double-minute 2 homologue


p38 mitogen-activated protein kinase (MAPK14)


E1A-binding protein, 300-kDa (EP300)


P300/CBP-associated factor


Protein kinase C (multiple isoforms)


Double-stranded RNA-dependent protein kinase (PRKR)


Protein inhibitor of activated STAT (multiple isoforms)


Peptidyl-prolyl-cis-trans isomerase 1


Ribosomal S6 kinase 2 (RPS6KA3)


SET domain-containing protein 9 (SET9)


Serine/threonine protein kinase 15


TATA-binding protein-associated factor 250-kD (TAF1)



This work was supported by the Center for HPC at Shanghai Jiao Tong University, the National Key Research and Development Program of China (2018YFC0310803 and 2017YFE0103300), the National Natural Science Foundation of China (31770771 and 31620103901), and the Medical Engineering Cross Fund of Shanghai Jiao Tong University (YG2015MS56 and YG2017MS08).


  1. 1.
    Changeux JP (1961) The feedback control mechanisms of biosynthetic L-threonine deaminase by L-isoleucine. Cold Spring Harb Symp Quant Biol 26:313–318PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Monod J, Jacob F (1961) Teleonomic mechanisms in cellular metabolism, growth, and differentiation. Cold Spring Harb Symp Quant Biol 26:389–401PubMedCrossRefGoogle Scholar
  3. 3.
    Monod J, Wyman J, Changeux JP (1965) On the nature of allosteric transitions: a plausible model. J Mol Biol 12:88–118PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Freiburger LA, Baettig OM, Sprules T, Berghuis AM, Auclair K, Mittermaier AK (2011) Competing allosteric mechanisms modulate substrate binding in a dimeric enzyme. Nat Struct Mol Biol 18(3):288–294PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Nussinov R, Tsai CJ, Ma B (2013) The underappreciated role of allostery in the cellular network. Annu Rev Biophys 42:169–189PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Koshland DE Jr, Nemethy G, Filmer D (1966) Comparison of experimental binding data and theoretical models in proteins containing subunits. Biochemistry 5(1):365–385PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Hilser VJ, Wrabl JO, Motlagh HN (2012) Structural and energetic basis of allostery. Annu Rev Biophys 41:585–609PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Nussinov R, Tsai CJ (2015) Allostery without a conformational change? Revisiting the paradigm. Curr Opin Struct Biol 30:17–24CrossRefGoogle Scholar
  9. 9.
    May LT, Leach K, Sexton PM, Christopoulos A (2007) Allosteric modulation of G protein-coupled receptors. Annu Rev Pharmacol Toxicol 47:1–51PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    van der Lee R, Buljan M, Lang B, Weatheritt RJ, Daughdrill GW, Dunker AK, Fuxreiter M, Gough J, Gsponer J, Jones DT, Kim PM, Kriwacki RW, Oldfield CJ, Pappu RV, Tompa P, Uversky VN, Wright PE, Babu MM (2014) Classification of intrinsically disordered regions and proteins. Chem Rev 114(13):6589–6631PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Csizmok V, Follis AV, Kriwacki RW, Forman-Kay JD (2016) Dynamic protein interaction networks and new structural paradigms in signaling. Chem Rev 116(11):6424–6462PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Bah A, Forman-Kay JD (2016) Modulation of intrinsically disordered protein function by post-translational modifications. J Biol Chem R115:695056Google Scholar
  13. 13.
    Haynes C, Oldfield CJ, Ji F, Klitgord N, Cusick ME, Radivojac P, Uversky VN, Vidal M, Iakoucheva LM (2006) Intrinsic disorder is a common feature of hub proteins from four eukaryotic interactomes. PLoS Comput Biol 2(8):e100PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Wright PE, Dyson HJ (2014) Intrinsically disordered proteins in cellular signalling and regulation. Nat Rev Mol Cell Biol 16:18CrossRefGoogle Scholar
  15. 15.
    Iakoucheva LM, Brown CJ, Lawson JD, Obradović Z, Dunker AK (2002) Intrinsic disorder in cell-signaling and cancer-associated proteins. J Mol Biol 323(3):573–584PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Flock T, Weatheritt RJ, Latysheva NS, Babu MM (2014) Controlling entropy to tune the functions of intrinsically disordered regions. Curr Opin Struct Biol 26:62–72PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Tompa P (2013) Multisteric regulation by structural disorder in modular signaling proteins: an extension of the concept of allostery. Chem Rev 114(13):6715–6732PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Gandhi TK, Zhong J, Mathivanan S, Karthick L, Chandrika KN, Mohan SS, Sharma S, Pinkert S, Nagaraju S, Periaswamy B, Mishra G, Nandakumar K, Shen B, Deshpande N, Nayak R, Sarker M, Boeke JD, Parmigiani G, Schultz J, Bader JS, Pandey A (2006) Analysis of the human protein interactome and comparison with yeast, worm and fly interaction datasets. Nat Genet 38(3):285–293PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksoz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE (2005) A human protein-protein interaction network: a resource for annotating the proteome. Cell 122(6):957–968PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Fraser HB, Hirsh AE, Steinmetz LM, Scharfe C, Feldman MW (2002) Evolutionary rate in the protein interaction network. Science (New York, NY) 296(5568):750–752CrossRefGoogle Scholar
  21. 21.
    Jeong H, Mason SP, Barabasi AL, Oltvai ZN (2001) Lethality and centrality in protein networks. Nature 411(6833):41–42PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Nevins JR, Ginsberg HS, Blanchard JM, Wilson MC, Darnell JE Jr (1979) Regulation of the primary expression of the early adenovirus transcription units. J Virol 32(3):727–733PubMedPubMedCentralGoogle Scholar
  23. 23.
    Stephens C, Harlow E (1987) Differential splicing yields novel adenovirus 5 E1A mRNAs that encode 30 kd and 35 kd proteins. EMBO J 6(7):2027–2035PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Ulfendahl PJ, Linder S, Kreivi JP, Nordqvist K, Sevensson C, Hultberg H, Akusjarvi G (1987) A novel adenovirus-2 E1A mRNA encoding a protein with transcription activation properties. EMBO J 6(7):2037–2044PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Culp JS, Webster LC, Friedman DJ, Smith CL, Huang WJ, Wu FY, Rosenberg M, Ricciardi RP (1988) The 289-amino acid E1A protein of adenovirus binds zinc in a region that is important for trans-activation. Proc Natl Acad Sci U S A 85(17):6450–6454PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Kimelman D, Miller JS, Porter D, Roberts BE (1985) E1a regions of the human adenoviruses and of the highly oncogenic simian adenovirus 7 are closely related. J Virol 53(2):399–409PubMedPubMedCentralGoogle Scholar
  27. 27.
    van Ormondt H, Maat J, Dijkema R (1980) Comparison of nucleotide sequences of the early E1a regions for subgroups A, B and C of human adenoviruses. Gene 12(1–2):63–76PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Lyons RH, Ferguson BQ, Rosenberg M (1987) Pentapeptide nuclear localization signal in adenovirus E1a. Mol Cell Biol 7(7):2451–2456PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Krippl B, Ferguson B, Rosenberg M, Westphal H (1984) Functions of purified E1A protein microinjected into mammalian cells. Proc Natl Acad Sci 81(22):6988–6992PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Harlow E, Whyte P, Franza BR Jr, Schley C (1986) Association of adenovirus early-region 1A proteins with cellular polypeptides. Mol Cell Biol 6(5):1579–1589PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Yee SP, Branton PE (1985) Detection of cellular proteins associated with human adenovirus type 5 early region 1A polypeptides. Virology 147(1):142–153PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Blobel GA (2000) CREB-binding protein and p300: molecular integrators of hematopoietic transcription. Blood 95(3):745–755PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Giordano A, Avantaggiati ML (1999) p300 and CBP: partners for life and death. J Cell Physiol 181(2):218–230PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Dyson HJ, Wright PE (2005) Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol 6(3):197–208PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Dyson HJ, Wright PE (2016) Role of intrinsic protein disorder in the function and interactions of the transcriptional coactivators CREB-binding protein (CBP) and p300. J Biol Chem 291(13):6714–6722PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Egan C, Bayley ST, Branton PE (1989) Binding of the Rb1 protein to E1A products is required for adenovirus transformation. Oncogene 4(3):383–388PubMedPubMedCentralGoogle Scholar
  37. 37.
    Whyte P, Buchkovich KJ, Horowitz JM, Friend SH, Raybuck M, Weinberg RA, Harlow E (1988) Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product. Nature 334(6178):124–129PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Chan HM, Krstic-Demonacos M, Smith L, Demonacos C, La Thangue NB (2001) Acetylation control of the retinoblastoma tumour-suppressor protein. Nat Cell Biol 3(7):667–674PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Subramanian T, Zhao LJ, Chinnadurai G (2013) Interaction of CtBP with adenovirus E1A suppresses immortalization of primary epithelial cells and enhances virus replication during productive infection. Virology 443(2):313–320PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Tremblay ML, Dumont DJ, Branton PE (1989) Analysis of phosphorylation sites in the exon 1 region of E1A proteins of human adenovirus type 5. Virology 169(2):397–407PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Hateboer G, Gennissen A, Ramos YF, Kerkhoven RM, Sonntag-Buck V, Stunnenberg HG, Bernards R (1995) BS69, a novel adenovirus E1A-associated protein that inhibits E1A transactivation. EMBO J 14(13):3159–3169PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Pines J, Hunter T (1990) Human cyclin A is adenovirus E1A-associated protein p60 and behaves differently from cyclin B. Nature 346(6286):760–763PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Ewen ME, Xing YG, Lawrence JB, Livingston DM (1991) Molecular cloning, chromosomal mapping, and expression of the cDNA for p107, a retinoblastoma gene product-related protein. Cell 66(6):1155–1164PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Tsai LH, Harlow E, Meyerson M (1991) Isolation of the human cdk2 gene that encodes the cyclin A- and adenovirus E1A-associated p33 kinase. Nature 353(6340):174–177PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Hannon GJ, Demetrick D, Beach D (1993) Isolation of the Rb-related p130 through its interaction with CDK2 and cyclins. Genes Dev 7(12a):2378–2391PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Li Y, Graham C, Lacy S, Duncan AM, Whyte P (1993) The adenovirus E1A-associated 130-kD protein is encoded by a member of the retinoblastoma gene family and physically interacts with cyclins A and E. Genes Dev 7(12a):2366–2377PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Cohen MJ, Yousef AF, Massimi P, Fonseca GJ, Todorovic B, Pelka P, Turnell AS, Banks L, Mymryk JS (2013) Dissection of the C-terminal region of E1A redefines the roles of CtBP and other cellular targets in oncogenic transformation. J Virol 87(18):10348–10355PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Geisberg JV, Lee WS, Berk AJ, Ricciardi RP (1994) The zinc finger region of the adenovirus E1A transactivating domain complexes with the TATA box binding protein. Proc Natl Acad Sci U S A 91(7):2488–2492PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Hateboer G, Timmers HT, Rustgi AK, Billaud M, van’t Veer LJ, Bernards R (1993) TATA-binding protein and the retinoblastoma gene product bind to overlapping epitopes on c-Myc and adenovirus E1A protein. Proc Natl Acad Sci U S A 90(18):8489–8493PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Song CZ, Loewenstein PM, Toth K, Green M (1995) Transcription factor TFIID is a direct functional target of the adenovirus E1A transcription-repression domain. Proc Natl Acad Sci U S A 92(22):10330–10333PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Boyer TG, Berk AJ (1993) Functional interaction of adenovirus E1A with holo-TFIID. Genes Dev 7(9):1810–1823PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Goodman RH, Smolik S (2000) CBP/p300 in cell growth, transformation, and development. Genes Dev 14(13):1553–1577PubMedPubMedCentralGoogle Scholar
  53. 53.
    Thakur JK, Yadav A, Yadav G (2013) Molecular recognition by the KIX domain and its role in gene regulation. Nucleic Acids Res 42(4):2112–2125PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Goto NK, Zor T, Martinez-Yamout M, Dyson HJ, Wright PE (2002) Cooperativity in transcription factor binding to the coactivator CREB-binding protein (CBP) The mixed lineage leukemia protein (MLL) activation domain binds to an allosteric site on the KIX domain. J Biol Chem 277(45):43168–43174PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Radhakrishnan I, Pérez-Alvarado GC, Parker D, Dyson HJ, Montminy MR, Wright PE (1997) Solution structure of the KIX domain of CBP bound to the transactivation domain of CREB: a model for activator: coactivator interactions. Cell 91(6):741–752PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    De Guzman RN, Goto NK, Dyson HJ, Wright PE (2006) Structural basis for cooperative transcription factor binding to the CBP coactivator. J Mol Biol 355(5):1005–1013PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Ernst P, Wang J, Huang M, Goodman RH, Korsmeyer SJ (2001) MLL and CREB bind cooperatively to the nuclear coactivator CREB-binding protein. Mol Cell Biol 21(7):2249–2258PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Kim PM, Sboner A, Xia Y, Gerstein M (2008) The role of disorder in interaction networks: a structural analysis. Mol Syst Biol 4:179PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Ferrari R, Pellegrini M, Horwitz GA, Xie W, Berk AJ, Kurdistani SK (2008) Epigenetic reprogramming by adenovirus e1a. Science 321(5892):1086–1088PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    White E (2001) Regulation of the cell cycle and apoptosis by the oncogenes of adenovirus. Oncogene 20(54):7836PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Ferreon JC, Martinez-Yamout MA, Dyson HJ, Wright PE (2009b) Structural basis for subversion of cellular control mechanisms by the adenoviral E1A oncoprotein. Proc Natl Acad Sci U S A 106(32):13260–13265PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Ferreon ACM, Ferreon JC, Wright PE, Deniz AA (2013) Modulation of allostery by protein intrinsic disorder. Nature 498(7454):390PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Anderson CW, Appella E (2009) Signaling to the p53 tumor suppressor through pathways activated by genotoxic and non-genotoxic stresses. In: Handbook of cell signaling, 2nd edn. Elsevier, pp 2185–2204Google Scholar
  64. 64.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253(5015):49–53PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Avalos JL, Celic I, Muhammad S, Cosgrove MS, Boeke JD, Wolberger C (2002) Structure of a Sir2 enzyme bound to an acetylated p53 peptide. Mol Cell 10(3):523–535PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Bochkareva E, Kaustov L, Ayed A, Yi G-S, Lu Y, Pineda-Lucena A, Liao JC, Okorokov AL, Milner J, Arrowsmith CH (2005) Single-stranded DNA mimicry in the p53 transactivation domain interaction with replication protein A. Proc Natl Acad Sci U S A 102(43):15412–15417PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Cho Y, Gorina S, Jeffrey PD, Pavletich NP (1994) Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265(5170):346–355PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Chuikov S, Kurash JK, Wilson JR, Xiao B, Justin N, Ivanov GS, McKinney K, Tempst P, Prives C, Gamblin SJ (2004) Regulation of p53 activity through lysine methylation. Nature 432(7015):353PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Di Lello P, Jenkins LMM, Jones TN, Nguyen BD, Hara T, Yamaguchi H, Dikeakos JD, Appella E, Legault P, Omichinski JG (2006) Structure of the Tfb1/p53 complex: Insights into the interaction between the p62/Tfb1 subunit of TFIIH and the activation domain of p53. Mol Cell 22(6):731–740PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Gorina S, Pavletich NP (1996) Structure of the p53 tumor suppressor bound to the ankyrin and SH3 domains of 53BP2. Science 274(5289):1001–1005PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Joo WS, Jeffrey PD, Cantor SB, Finnin MS, Livingston DM, Pavletich NP (2002) Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure. Genes Dev 16(5):583–593PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, Pavletich NP (1996) Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274(5289):948–953PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Kuszewski J, Gronenborn AM, Clore GM (1999) Improving the packing and accuracy of NMR structures with a pseudopotential for the radius of gyration. J Am Chem Soc 121(10):2337–2338CrossRefGoogle Scholar
  74. 74.
    Lilyestrom W, Klein MG, Zhang R, Joachimiak A, Chen XS (2006) Crystal structure of SV40 large T-antigen bound to p53: interplay between a viral oncoprotein and a cellular tumor suppressor. Genes Dev 20(17):2373–2382PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Lowe ED, Tews I, Cheng KY, Brown NR, Gul S, Noble ME, Gamblin SJ, Johnson LN (2002) Specificity determinants of recruitment peptides bound to phospho-CDK2/cyclin A. Biochemistry 41(52):15625–15634PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Mujtaba S, He Y, Zeng L, Yan S, Plotnikova O, Sanchez R, Zeleznik-Le NJ, Ze R, Zhou M-M (2004) Structural mechanism of the bromodomain of the coactivator CBP in p53 transcriptional activation. Mol Cell 13(2):251–263PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Obsil T, Ghirlando R, Klein DC, Ganguly S, Dyda F (2001) Crystal structure of the 14-3-3ζ: serotonin N-acetyltransferase complex: a role for scaffolding in enzyme regulation. Cell 105(2):257–267PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Petosa C, Masters SC, Bankston LA, Pohl J, Wang B, Fu H, Liddington RC (1998) 14-3-3ζ binds a phosphorylated Raf peptide and an unphosphorylated peptide via its conserved amphipathic groove. J Biol Chem 273(26):16305–16310PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Poux AN, Marmorstein R (2003) Molecular basis for Gcn5/PCAF histone acetyltransferase selectivity for histone and nonhistone substrates. Biochemistry 42(49):14366–14374CrossRefGoogle Scholar
  80. 80.
    Rittinger K, Budman J, Xu J, Volinia S, Cantley LC, Smerdon SJ, Gamblin SJ, Yaffe MB (1999) Structural analysis of 14-3-3 phosphopeptide complexes identifies a dual role for the nuclear export signal of 14-3-3 in ligand binding. Mol Cell 4(2):153–166PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Wu H, Maciejewski MW, Marintchev A, Benashski SE, Mullen GP, King SM (2000) Solution structure of a dynein motor domain associated light chain. Nat Struct Mol Biol 7(7):575CrossRefGoogle Scholar
  82. 82.
    Dawson R, Müller L, Dehner A, Klein C, Kessler H, Buchner J (2003) The N-terminal domain of p53 is natively unfolded. J Mol Biol 332(5):1131–1141PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Lee H, Mok KH, Muhandiram R, Park K-H, Suk J-E, Kim D-H, Chang J, Sung YC, Choi KY, Han K-H (2000) Local structural elements in the mostly unstructured transcriptional activation domain of human p53. J Biol Chem 275(38):29426–29432PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN (2005) Flexible nets. FEBS J 272(20):5129–5148PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Dunker AK, Garner E, Guilliot S, Romero P, Albrecht K, Hart J, Obradovic Z, Kissinger C, Villafranca JE (1998) Protein disorder and the evolution of molecular recognition: theory, predictions and observations. In: Pacific symposium on biocomputing, pp 473–484Google Scholar
  86. 86.
    Uversky VN, Oldfield CJ, Dunker AK (2005) Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling. J Mol Recognit 18(5):343–384PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Ferreon JC, Lee CW, Arai M, Martinez-Yamout MA, Dyson HJ, Wright PE (2009a) Cooperative regulation of p53 by modulation of ternary complex formation with CBP/p300 and HDM2. Proc Natl Acad Sci U S A 106(16):6591–6596PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Teufel DP, Freund SM, Bycroft M, Fersht AR (2007) Four domains of p300 each bind tightly to a sequence spanning both transactivation subdomains of p53. Proc Natl Acad Sci U S A 104(17):7009–7014PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Feng H, Jenkins LMM, Durell SR, Hayashi R, Mazur SJ, Cherry S, Tropea JE, Miller M, Wlodawer A, Appella E (2009) Structural basis for p300 Taz2-p53 TAD1 binding and modulation by phosphorylation. Structure 17(2):202–210PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Miller Jenkins LM, Feng H, Durell SR, Tagad HD, Mazur SJ, Tropea JE, Bai Y, Appella E (2015) Characterization of the p300 Taz2–p53 TAD2 complex and comparison with the p300 Taz2–p53 TAD1 complex. Biochemistry 54(11):2001–2010PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Popowicz G, Czarna A, Holak T (2008) Structure of the human Mdmx protein bound to the p53 tumor suppressor transactivation domain. Cell Cycle 7(15):2441–2443PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Vise PD, Baral B, Latos AJ, Daughdrill GW (2005) NMR chemical shift and relaxation measurements provide evidence for the coupled folding and binding of the p53 transactivation domain. Nucleic Acids Res 33(7):2061–2077PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Wells M, Tidow H, Rutherford TJ, Markwick P, Jensen MR, Mylonas E, Svergun DI, Blackledge M, Fersht AR (2008) Structure of tumor suppressor p53 and its intrinsically disordered N-terminal transactivation domain. Proc Natl Acad Sci U S A 105(15):5762–5767PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Borcherds W, Theillet F-X, Katzer A, Finzel A, Mishall KM, Powell AT, Wu H, Manieri W, Dieterich C, Selenko P (2014) Disorder and residual helicity alter p53-Mdm2 binding affinity and signaling in cells. Nat Chem Biol 10(12):1000PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Pejaver V, Hsu WL, Xin F, Dunker AK, Uversky VN, Radivojac P (2014) The structural and functional signatures of proteins that undergo multiple events of post-translational modification. Protein Sci 23(8):1077–1093PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Gao J, Xu D (2012) Correlation between posttranslational modification and intrinsic disorder in protein. In: Biocomputing 2012. World Scientific, pp 94–103Google Scholar
  97. 97.
    Theillet F-X, Smet-Nocca C, Liokatis S, Thongwichian R, Kosten J, Yoon M-K, Kriwacki RW, Landrieu I, Lippens G, Selenko P (2012) Cell signaling, post-translational protein modifications and NMR spectroscopy. J Biomol NMR 54(3):217–236PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Tsai C-J, Ma B, Nussinov R (2009) Protein–protein interaction networks: how can a hub protein bind so many different partners? Trends Biochem Sci 34(12):594–600PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Lee CW, Ferreon JC, Ferreon ACM, Arai M, Wright PE (2010) Graded enhancement of p53 binding to CREB-binding protein (CBP) by multisite phosphorylation. Proc Natl Acad Sci U S A 107(45):19290–19295PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Schon O, Friedler A, Bycroft M, Freund SM, Fersht AR (2002) Molecular mechanism of the interaction between MDM2 and p53. J Mol Biol 323(3):491–501PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Kohn KW, Pommier Y (2005) Molecular interaction map of the p53 and Mdm2 logic elements, which control the Off–On switch of p53 in response to DNA damage. Biochem Biophys Res Commun 331(3):816–827PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Berger M, Stahl N, Del Sal G, Haupt Y (2005) Mutations in proline 82 of p53 impair its activation by Pin1 and Chk2 in response to DNA damage. Mol Cell Biol 25(13):5380–5388PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Brooks CL, Gu W (2003) Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. Curr Opin Cell Biol 15(2):164–171PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Kawaguchi Y, Ito A, Appella E, Yao T-P (2006) Charge modification at multiple C-terminal lysine residues regulates p53 oligomerization and its nucleus-cytoplasm trafficking. J Biol Chem 281(3):1394–1400PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Appella E, Anderson CW (2001) Post-translational modifications and activation of p53 by genotoxic stresses. Eur J Biochem 268(10):2764–2772PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Di Stefano V, Soddu S, Sacchi A, D'orazi G (2005) HIPK2 contributes to PCAF-mediated p53 acetylation and selective transactivation of p21 Waf1 after nonapoptotic DNA damage. Oncogene 24(35):5431PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Rodriguez MS, Desterro JM, Lain S, Lane DP, Hay RT (2000) Multiple C-terminal lysine residues target p53 for ubiquitin-proteasome-mediated degradation. Mol Cell Biol 20(22):8458–8467PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Dornan D, Bheddah S, Newton K, Ince W, Frantz GD, Dowd P, Koeppen H, Dixit VM, French DM (2004) COP1, the negative regulator of p53, is overexpressed in breast and ovarian adenocarcinomas. Cancer Res 64(20):7226–7230PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Esser C, Scheffner M, Höhfeld J (2005) The chaperone associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation. J Biol ChemGoogle Scholar
  110. 110.
    Nikolaev AY, Li M, Puskas N, Qin J, Gu W (2003) Parc: a cytoplasmic anchor for p53. Cell 112(1):29–40PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Leng RP, Lin Y, Ma W, Wu H, Lemmers B, Chung S, Parant JM, Lozano G, Hakem R, Benchimol S (2003) Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell 112(6):779–791PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Schmidt D, Müller S (2002) Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proc Natl Acad Sci U S A 99(5):2872–2877PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Xirodimas DP, Saville MK, Bourdon J-C, Hay RT, Lane DP (2004) Mdm2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity. Cell 118(1):83–97PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Liu H, Song D, Lu H, Luo R, Chen HF (2018) Intrinsically disordered protein specific force field CHARMM 36 IDPSFF. Chem Biol Drug Des 92(4):1722–1735PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Song D, Luo R, Chen H-F (2017a) The IDP-specific force field ff14IDPSFF improves the conformer sampling of intrinsically disordered proteins. J Chem Inf Model 57(5):1166–1178PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Song D, Wang W, Ye W, Ji D, Luo R, Chen HF (2017b) ff14IDPs force field improving the conformation sampling of intrinsically disordered proteins. Chem Biol Drug Des 89(1):5–15PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Wang W, Ye W, Jiang C, Luo R, Chen HF (2014) New force field on modeling intrinsically disordered proteins. Chem Biol Drug Des 84(3):253–269PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Ye W, Ji D, Wang W, Luo R, Chen H-F (2015) Test and evaluation of ff99IDPs force field for intrinsically disordered proteins. J Chem Inf Model 55(5):1021–1029PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Ashfaq Ur Rehman
    • 1
    • 2
  • Mueed Ur Rahman
    • 1
  • Taaha Arshad
    • 1
  • Hai-Feng Chen
    • 1
    • 3
    Email author
  1. 1.State Key Laboratory of Microbial Metabolism, Department of Bioinformatics and Biostatistics, National Experimental Teaching Center for Life Sciences and Biotechnology, School of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghaiChina
  2. 2.Department of BiochemistryAbdul Wali Khan University MardanMardanPakistan
  3. 3.Shanghai Center for Bioinformation TechnologyShanghaiChina

Personalised recommendations