Intrinsically disordered proteins (IDPs) and IDP regions fail to form a stable structure, yet they exhibit biological activities. Their mobile flexibility and structural instability are encoded by their amino acid sequences. They recognize proteins, nucleic acids, and other types of partners; they accelerate interactions and chemical reactions between bound partners; and they help accommodate posttranslational modifications, alternative splicing, protein fusions, and insertions or deletions. Overall, IDP-associated biological activities complement those of structured proteins. Recently, there has been an explosion of studies on IDP regions and their functions, yet the discovery and investigation of these proteins have a long, mostly ignored history. Along with recent discoveries, we present several early examples and the mechanisms by which IDPs contribute to function, which we hope will encourage comprehensive discussion of IDPs and IDP regions in biochemistry textbooks. Finally, we propose future directions for IDP research.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Dunker AK, Babu MM, Barbar E, Blackledge M, Bondos SE. 1.  et al. 2013. What's in a name? Why these proteins are intrinsically disordered. Intrinsically Disord. Proteins 1e24157
  2. Jirgensons B.2.  1966. Classification of proteins according to conformation. Makromol. Chem. 91:74–86 [Google Scholar]
  3. Arnone A, Bier CJ, Cotton FA, Day VW, Hazen EE Jr. 3.  et al. 1971. A high resolution structure of an inhibitor complex of the extracellular nuclease of Staphylococcus aureus. I. Experimental procedures and chain tracing. J. Biol. Chem. 246:2302–16 [Google Scholar]
  4. Uversky VN, Oldfield CJ, Dunker AK. 4.  2005. Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling. J. Mol. Recognit. 18:343–84 [Google Scholar]
  5. Wright PE, Dyson HJ. 5.  1999. Intrinsically unstructured proteins: re-assessing the protein structure–function paradigm. J. Mol. Biol. 293:321–31 [Google Scholar]
  6. Uversky VN, Narizhneva NV, Ivanova TV, Tomashevski AY. 6.  1997. Rigidity of human α-fetoprotein tertiary structure is under ligand control. Biochemistry 36:13638–45 [Google Scholar]
  7. Johnson LN.7.  1992. Glycogen phosphorylase: control by phosphorylation and allosteric effectors. FASEB J. 6:2274–82 [Google Scholar]
  8. Reichmann D, Jakob U. 8.  2013. The roles of conditional disorder in redox proteins. Curr. Opin. Struct. Biol. 23:436–42 [Google Scholar]
  9. Qian YQ, Otting G, Furukubo-Tokunaga K, Affolter M, Gehring WJ, Wüthrich K. 9.  1992. NMR structure determination reveals that the homeodomain is connected through a flexible linker to the main body in the Drosophila antennapedia protein. Proc. Natl. Acad. Sci. USA 89:10738–42 [Google Scholar]
  10. Trombitás K, Greaser M, Labeit S, Jin J-P, Kellermayer M. 10.  et al. 1998. Titin extensibility in situ: entropic elasticity of permanently folded and permanently unfolded molecular segments. J. Cell Biol. 140:853–59 [Google Scholar]
  11. Rauscher S, Pomès R. 11.  2012. Structural disorder and protein elasticity. Fuzziness M Fuxreiter, P Tompa 159–83 New York: Springer [Google Scholar]
  12. Hoh JH.12.  1998. Functional protein domains from the thermally driven motion of polypeptide chains: a proposal. Proteins 32:223–28 [Google Scholar]
  13. Uversky VN, Narizhneva NV, Ivanova TV, Kirkitadze MD, Tomashevski AY. 13.  1997. Ligand-free form of human α-fetoprotein: evidence for the molten globule state. FEBS Lett. 410:280–84 [Google Scholar]
  14. Ebert M-O, Bae S-H, Dyson HJ, Wright PE. 14.  2008. NMR relaxation study of the complex formed between CBP and the activation domain of the nuclear hormone receptor coactivator ACTR. Biochemistry 47:1299–308 [Google Scholar]
  15. Dunker AK, Obradović Z. 15.  2001. The protein trinity—linking function and disorder. Nat. Biotechnol. 19:805–6 [Google Scholar]
  16. Holmes KC.16.  1983. Flexibility in tobacco mosaic virus. Ciba Found. Symp. 93:116–38 [Google Scholar]
  17. Dunker AK, Lawson JD, Brown CJ, Williams RM, Romero P. 17.  et al. 2001. Intrinsically disordered protein. J. Mol. Graph. Model. 19:26–59 [Google Scholar]
  18. Romero PR, Zaidi S, Fang YY, Uversky VN, Radivojac P. 18.  et al. 2006. Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms. Proc. Natl. Acad. Sci. USA 103:8390–95 [Google Scholar]
  19. Inobe T, Fishbain S, Prakash S, Matouschek A. 19.  2011. Defining the geometry of the two-component proteasome degron. Nat. Chem. Biol. 7:161–67 [Google Scholar]
  20. Gao J, Xu D. 20.  2012. Correlation between posttranslational modification and intrinsic disorder in protein. Pac. Symp. Biocomput. 1:94–103 [Google Scholar]
  21. Rancurel C, Khosravi M, Dunker AK, Romero PR, Karlin D. 21.  2009. Overlapping genes produce proteins with unusual sequence properties and offer insight into de novo protein creation. J. Virol. 83:10719–36 [Google Scholar]
  22. Kovacs E, Tompa P, Liliom K, Kalmar L. 22.  2010. Dual coding in alternative reading frames correlates with intrinsic protein disorder. Proc. Natl. Acad. Sci. USA 107:5429–34 [Google Scholar]
  23. Hegyi H, Buday L, Tompa P. 23.  2009. Intrinsic structural disorder confers cellular viability on oncogenic fusion proteins. PLoS Comput. Biol. 5:e1000552 [Google Scholar]
  24. Light S, Sagit R, Ekman D, Elofsson A. 24.  2013. Long indels are disordered: a study of disorder and indels in homologous eukaryotic proteins. Biochim. Biophys. Acta 1834:890–97 [Google Scholar]
  25. Brown CJ, Johnson AK, Dunker AK, Daughdrill GW. 25.  2011. Evolution and disorder. Curr. Opin. Struct. Biol. 21:441–46 [Google Scholar]
  26. Mao AH, Crick SL, Vitalis A, Chicoine CL, Pappu RV. 26.  2010. Net charge per residue modulates conformational ensembles of intrinsically disordered proteins. Proc. Natl. Acad. Sci. USA 107:8183–88 [Google Scholar]
  27. Das RK, Pappu RV. 27.  2013. Conformations of intrinsically disordered proteins are influenced by linear sequence distributions of oppositely charged residues. Proc. Natl. Acad. Sci. USA 110:13392–97 [Google Scholar]
  28. Tran HT, Mao A, Pappu RV. 28.  2008. Role of backbone-solvent interactions in determining conformational equilibria of intrinsically disordered proteins. J. Am. Chem. Soc. 130:7380–92 [Google Scholar]
  29. Crick SL, Jayaraman M, Frieden C, Wetzel R, Pappu RV. 29.  2006. Fluorescence correlation spectroscopy shows that monomeric polyglutamine molecules form collapsed structures in aqueous solutions. Proc. Natl. Acad. Sci. USA 103:16764–69 [Google Scholar]
  30. Uversky VN, Ptitsyn OB. 30.  1996. Further evidence on the equilibrium “pre-molten globule state”: four-state guanidinium chloride–induced unfolding of carbonic anhydrase B at low temperature. J. Mol. Biol. 255:215–28 [Google Scholar]
  31. Ptitsyn OB, Bychkova VE, Uversky VN. 31.  1995. Kinetic and equilibrium folding intermediates. Philos. Trans. R. Soc. Lond. B 348:35–41 [Google Scholar]
  32. Srivastava AK, Sharma Y, Chary KVR. 32.  2010. A natively unfolded βγ-crystallin domain from Hahella chejuensis. Biochemistry 49:9746–55 [Google Scholar]
  33. Choy WY, Forman-Kay JD. 33.  2001. Calculation of ensembles of structures representing the unfolded state of an SH3 domain. J. Mol. Biol. 308:1011–32 [Google Scholar]
  34. Jensen MR, Ruigrok RWH, Blackledge M. 34.  2013. Describing intrinsically disordered proteins at atomic resolution by NMR. Curr. Opin. Struct. Biol. 23:426–35 [Google Scholar]
  35. Dunker AK, Kriwacki RW. 35.  2011. The orderly chaos of proteins. Sci. Am. 304:68–73 [Google Scholar]
  36. Murzin AG, Brenner SE, Hubbard T, Chothia C. 36.  1995. SCOP: a structural classification of proteins database for the investigation of sequences and structures. J. Mol. Biol. 247:536–40 [Google Scholar]
  37. Orengo CA, Michie AD, Jones S, Jones DT, Swindells MB, Thornton JM. 37.  1997. CATH—a hierarchic classification of protein domain structures. Structure 5:1093–108 [Google Scholar]
  38. Vucetic S, Brown CJ, Dunker AK, Obradović Z. 38.  2003. Flavors of protein disorder. Proteins 52:573–84 [Google Scholar]
  39. Yegambaram K, Bulloch EM, Kingston RL. 39.  2013. Protein domain definition should allow for conditional disorder. Protein Sci. 22:1502–18 [Google Scholar]
  40. Bardwell JCA, Jakob U. 40.  2012. Conditional disorder in chaperone action. Trends Biochem. Sci. 37:517–25 [Google Scholar]
  41. Zhang T, Faraggi E, Li Z, Zhou Y. 41.  2013. Intrinsically semi-disordered state and its role in induced folding and protein aggregation. Cell Biochem. Biophys. 67:1193–205 [Google Scholar]
  42. McMeekin TL.42.  1952. Milk proteins. J. Food Prot. 15:57–63 [Google Scholar]
  43. Jirgensons B.43.  1958. Optical rotation and viscosity of native and denatured proteins. X. Further studies on optical rotatory dispersion. Arch. Biochem. Biophys. 74:57–69 [Google Scholar]
  44. Doolittle RF.44.  1973. Structural aspects of the fibrinogen to fibrin conversion. Adv. Protein Chem. 27:1–109 [Google Scholar]
  45. Bode W, Fehlhammer H, Huber R. 45.  1976. Crystal structure of bovine trypsinogen at 1–8 Å resolution. I. Data collection, application of patterson search techniques and preliminary structural interpretation. J. Mol. Biol. 106:325–35 [Google Scholar]
  46. Manalan AS, Klee CB. 46.  1983. Activation of calcineurin by limited proteolysis. Proc. Natl. Acad. Sci. USA 80:4291–95 [Google Scholar]
  47. Holt C, Carver JA, Ecroyd H, Thorn DC. 47.  2013. Caseins and the casein micelle: their biological functions, structures and behaviour in foods. J. Dairy Sci. 96:6127–46 [Google Scholar]
  48. Horne DS.48.  2006. Casein micelle structure: models and muddles. Curr. Opin. Colloid Interface Sci. 11:148–53 [Google Scholar]
  49. Holt C, Timmins PA, Errington N, Leaver J. 49.  1998. A core-shell model of calcium phosphate nanoclusters stabilized by β-casein phosphopeptides, derived from sedimentation equilibrium and small-angle X-ray and neutron-scattering measurements. Eur. J. Biochem. 252:73–78 [Google Scholar]
  50. De Kruif CG, Huppertz T, Urban VS, Petukhov AV. 50.  2012. Casein micelles and their internal structure. Adv. Colloid Interface Sci. 171/17236–52
  51. Holt C.51.  2013. Unfolded phosphopolypeptides enable soft and hard tissues to coexist in the same organism with relative ease. Curr. Opin. Struct. Biol. 23:420–25 [Google Scholar]
  52. Holt C, Sørensen ES, Clegg RA. 52.  2009. Role of calcium phosphate nanoclusters in the control of calcification. FEBS J. 276:2308–23 [Google Scholar]
  53. Byrne BM, van het Schip AD, van de Klundert JA, Arnberg AC, Gruber M, Ab G. 53.  1984. Amino acid sequence of phosvitin derived from the nucleotide sequence of part of the chicken vitellogenin gene. Biochemistry 23:4275–79 [Google Scholar]
  54. Oldfield CJ, Xue B, Van Y-Y, Ulrich EL, Markley JL. 54.  et al. 2013. Utilization of protein intrinsic disorder knowledge in structural proteomics. Biochim. Biophys. Acta 1834:487–98 [Google Scholar]
  55. Doolittle RF, Kollman JM. 55.  2006. Natively unfolded regions of the vertebrate fibrinogen molecule. Proteins 63:391–97 [Google Scholar]
  56. Brown CJ, Takayama S, Campen AM, Vise P, Marshall TW. 56.  et al. 2002. Evolutionary rate heterogeneity in proteins with long disordered regions. J. Mol. Evol. 55:104–10 [Google Scholar]
  57. Fukuchi S, Homma K, Minezaki Y, Nishikawa K. 57.  2006. Intrinsically disordered loops inserted into the structural domains of human proteins. J. Mol. Biol. 355:845–57 [Google Scholar]
  58. Tsurupa G, Mahid A, Veklich Y, Weisel JW, Medved L. 58.  2011. Structure, stability, and interaction of fibrin αC-domain polymers. Biochemistry 50:8028–37 [Google Scholar]
  59. Marsh JJ, Guan HS, Li S, Chiles PG, Tran D, Morris TA. 59.  2013. Structural insights into fibrinogen dynamics using amide hydrogen/deuterium exchange mass spectrometry. Biochemistry 52:5491–502 [Google Scholar]
  60. Kriwacki RW, Hengst L, Tennant L, Reed SI, Wright PE. 60.  1996. Structural studies of p21Waf1/Cip1/Sdi1 in the free and Cdk2-bound state: conformational disorder mediates binding diversity. Proc. Natl. Acad. Sci. USA 93:11504–9 [Google Scholar]
  61. Hsu W-L, Oldfield CJ, Xue B, Meng J, Huang F. 61.  et al. 2013. Exploring the binding diversity of intrinsically disordered proteins involved in one-to-many binding. Protein Sci. 22:258–73 [Google Scholar]
  62. Baratti J, Maroux S, Louvard D. 62.  1973. Effect of ionic strength and calcium ions on the activation of trypsinogen by enterokinase. A modified test for the quantitative evaluation of this enzyme. Biochim. Biophys. Acta 321:632–38 [Google Scholar]
  63. Bode W, Huber R. 63.  1976. Induction of the bovine trypsinogen–trypsin transition by peptides sequentially similar to the N-terminus of trypsin. FEBS Lett. 68:231–36 [Google Scholar]
  64. Klee CB, Crouch TH, Krinks MH. 64.  1979. Calcineurin: a calcium- and calmodulin-binding protein of the nervous system. Proc. Natl. Acad. Sci. USA 76:6270–73 [Google Scholar]
  65. Stewart AA, Ingebritsen TS, Manalan A, Klee CB, Cohen P. 65.  1982. Discovery of a Ca2+- and calmodulin-dependent protein phosphatase: probable identity with calcineurin (CaM-BP80). FEBS Lett. 137:80–84 [Google Scholar]
  66. Kissinger CR, Parge HE, Knighton DR, Lewis CT, Pelletier LA. 66.  et al. 1995. Crystal structures of human calcineurin and the human FKBP12–FK506–calcineurin complex. Nature 378:641–44 [Google Scholar]
  67. Martínez-Martínez S, Redondo JM. 67.  2004. Inhibitors of the calcineurin/NFAT pathway. Curr. Med. Chem. 11:997–1007 [Google Scholar]
  68. Radivojac P, Vucetic S, O'Connor TR, Uversky VN, Obradović Z, Dunker AK. 68.  2006. Calmodulin signaling: analysis and prediction of a disorder-dependent molecular recognition. Proteins 63:398–410 [Google Scholar]
  69. Meador WE, Means AR, Quiocho FA. 69.  1993. Modulation of calmodulin plasticity in molecular recognition on the basis of X-ray structures. Science 262:1718–21 [Google Scholar]
  70. Rumi-Masante J, Rusinga FI, Lester TE, Dunlap TB, Williams TD. 70.  et al. 2012. Structural basis for activation of calcineurin by calmodulin. J. Mol. Biol. 415:307–17 [Google Scholar]
  71. Cavanagh J, Fairbrother WJ, Palmer AG III, Rance M, Skelton NJ.71.  2010. Protein NMR Spectroscopy: Principles and Practice San Diego: Elsevier
  72. Daughdrill GW, Chadsey MS, Karlinsey JE, Hughes KT, Dahlquist FW. 72.  1997. The C-terminal half of the anti-σ factor, FlgM, becomes structured when bound to its target, σ 28. Nat. Struct. Mol. Biol. 4:285–91 [Google Scholar]
  73. Allison JR, Varnai P, Dobson CM, Vendruscolo M. 73.  2009. Determination of the free energy landscape of α-synuclein using spin label nuclear magnetic resonance measurements. J. Am. Chem. Soc. 131:18314–26 [Google Scholar]
  74. Gehring WJ, Qian YQ, Billeter M, Furukubo-Tokunaga K, Schier AF. 74.  et al. 1994. Homeodomain-DNA recognition. Cell 78:211–23 [Google Scholar]
  75. Martin AJM, Walsh I, Tosatto SCE. 75.  2010. MOBI: a web server to define and visualize structural mobility in NMR protein ensembles. Bioinformatics 26:2916–17 [Google Scholar]
  76. Ota M, Koike R, Amemiya T, Tenno T, Romero PR. 76.  et al. 2013. An assignment of intrinsically disordered regions of proteins based on NMR structures. J. Struct. Biol. 181:29–36 [Google Scholar]
  77. Larsson G, Martinez G, Schleucher J, Wijmenga SS. 77.  2003. Detection of nano-second internal motion and determination of overall tumbling times independent of the time scale of internal motion in proteins from NMR relaxation data. J. Biomol. NMR 27:291–312 [Google Scholar]
  78. Muchmore SW, Sattler M, Liang H, Meadows RP, Harlan JE. 78.  et al. 1996. X-ray and NMR structure of human Bcl-XL, an inhibitor of programmed cell death. Nature 381:335–41 [Google Scholar]
  79. Ito Y, Selenko P. 79.  2010. Cellular structural biology. Curr. Opin. Struct. Biol. 20:640–48 [Google Scholar]
  80. Dedmon MM, Patel CN, Young GB, Pielak GJ. 80.  2002. FlgM gains structure in living cells. Proc. Natl. Acad. Sci. USA 99:12681–84 [Google Scholar]
  81. Selenko P, Wagner G. 81.  2007. Looking into live cells with in-cell NMR spectroscopy. J. Struct. Biol. 158:244–53 [Google Scholar]
  82. Binolfi A, Theillet F-X, Selenko P. 82.  2012. Bacterial in-cell NMR of human α-synuclein: a disordered monomer by nature?. Biochem. Soc. Trans. 40:950–54 [Google Scholar]
  83. Li C, Charlton LM, Lakkavaram A, Seagle C, Wang G. 83.  et al. 2008. Differential dynamical effects of macromolecular crowding on an intrinsically disordered protein and a globular protein: implications for in-cell NMR spectroscopy. J. Am. Chem. Soc. 130:6310–11 [Google Scholar]
  84. Barnes CO, Pielak GJ. 84.  2011. In-cell protein NMR and protein leakage. Proteins Struct. Funct. Bioinform. 79:347–51 [Google Scholar]
  85. Xie Q, Arnold G, Romero P, Obradović Z, Garner E, Dunker A. 85.  1998. The sequence attribute method for determining relationships between sequence and protein disorder. Workshop Genome Inform. 9:193–200 [Google Scholar]
  86. Dunker AK, Brown CJ, Obradović Z. 86.  2002. Identification and functions of usefully disordered proteins. Adv. Protein Chem. 62:25–49 [Google Scholar]
  87. Theillet FX, Kalmar L, Tompa P, Han KY, Selenko P. 87.  et al. 2013. The alphabet of intrinsic disorder. 1. Act like a pro: on the abundance and roles of proline residues in intrinsically disordered regions. Intrinsically Disord. Proteins 1:e24360 [Google Scholar]
  88. Vacic V, Uversky VN, Dunker AK, Lonardi S. 88.  2007. Composition profiler: a tool for discovery and visualization of amino acid composition differences. BMC Bioinform. 8:211 [Google Scholar]
  89. Hobohm U, Sander C. 89.  1994. Enlarged representative set of protein structures. Protein Sci. 3:522–24 [Google Scholar]
  90. Romero P, Obradović Z, Kissinger C, Villafranca JE, Dunker AK. 90.  1997. Identifying disordered regions in proteins from amino acid sequence. Int. Conf. Neural Netw. 1997:90–95 [Google Scholar]
  91. Romero P, Obradović Z, Dunker AK. 91.  1997. Sequence data analysis for long disordered regions prediction in the calcineurin family. Workshop Genome Inform. 8:110–24 [Google Scholar]
  92. Uversky VN, Gillespie JR, Fink AL. 92.  2000. Why are “natively unfolded” proteins unstructured under physiologic conditions?. Proteins 41:415–27 [Google Scholar]
  93. Dosztányi Z, Csizmók V, Tompa P, Simon I. 93.  2005. The pairwise energy content estimated from amino acid composition discriminates between folded and intrinsically unstructured proteins. J. Mol. Biol. 347:827–39 [Google Scholar]
  94. Li X, Romero P, Rani M, Dunker AK, Obradović Z. 94.  1999. Predicting protein disorder for N-, C-, and internal regions. Workshop Genome Inform. 10:30–40 [Google Scholar]
  95. Romero P, Obradović Z, Li X, Garner EC, Brown CJ, Dunker AK. 95.  2001. Sequence complexity of disordered protein. Proteins 42:38–48 [Google Scholar]
  96. Peng K, Radivojac P, Vucetic S, Dunker AK, Obradović Z. 96.  2006. Length-dependent prediction of protein intrinsic disorder. BMC Bioinform. 7:208 [Google Scholar]
  97. Dosztányi Z, Sándor M, Tompa P, Simon I. 97.  2007. Prediction of protein disorder at the domain level. Curr. Protein Pept. Sci. 8:161–71 [Google Scholar]
  98. He B, Wang K, Liu Y, Xue B, Uversky VN, Dunker AK. 98.  2009. Predicting intrinsic disorder in proteins: an overview. Cell Res. 19:929–49 [Google Scholar]
  99. Jin F, Liu Z. 99.  2013. Inherent relationships among different biophysical prediction methods for intrinsically disordered proteins. Biophys. J. 104:488–95 [Google Scholar]
  100. Huang F.100.  2013. Optimizing hydropathy scale to improve IDP prediction and characterizing IDPs' functions PhD thesis. Indiana Univ., Indianapolis 121
  101. Prilusky J, Felder CE, Zeev-Ben-Mordehai T, Rydberg EH, Man O. 101.  et al. 2005. FoldIndex: a simple tool to predict whether a given protein sequence is intrinsically unfolded. Bioinformatics 21:3435–38 [Google Scholar]
  102. Dosztányi Z, Csizmok V, Tompa P, Simon I. 102.  2005. IUPred: web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content. Bioinformatics 21:3433–34 [Google Scholar]
  103. Monastyrskyy B, Fidelis K, Moult J, Tramontano A, Kryshtafovych A. 103.  2011. Evaluation of disorder predictions in CASP9. Proteins Struct. Funct. Bioinform. 79:107–18 [Google Scholar]
  104. Monastyrskyy B, Kryshtafovych A, Moult J, Tramontano A, Fidelis K. 104.  2014. Assessment of protein disorder region predictions in CASP10. Proteins 82Suppl. 2) 127–37
  105. Romero P, Obradović Z, Kissinger CR, Villafranca JE, Garner E. 105.  et al. 1998. Thousands of proteins likely to have long disordered regions. Pac. Symp. Biocomput. 3:437–48 [Google Scholar]
  106. Dunker AK, Obradović Z, Romero P, Garner EC, Brown CJ. 106.  2000. Intrinsic protein disorder in complete genomes. Workshop Genome Inform. 11:161–71 [Google Scholar]
  107. Ward JJ, Sodhi JS, McGuffin LJ, Buxton BF, Jones DT. 107.  2004. Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J. Mol. Biol. 337:635–45 [Google Scholar]
  108. Xue B, Dunker AK, Uversky VN. 108.  2012. Orderly order in protein intrinsic disorder distribution: disorder in 3,500 proteomes from viruses and the three domains of life. J. Biomol. Struct. Dyn. 30:137–49 [Google Scholar]
  109. Iakoucheva LM, Brown CJ, Lawson JD, Obradović Z, Dunker AK. 109.  2002. Intrinsic disorder in cell-signaling and cancer-associated proteins. J. Mol. Biol. 323:573–84 [Google Scholar]
  110. Uversky VN, Oldfield CJ, Dunker AK. 110.  2008. Intrinsically disordered proteins in human diseases: introducing the D2 concept. Annu. Rev. Biophys. 37:215–46 [Google Scholar]
  111. Vacic V, Markwick PRL, Oldfield CJ, Zhao X, Haynes C. 111.  et al. 2012. Disease-associated mutations disrupt functionally important regions of intrinsic protein disorder. PLoS Comput. Biol. 8:e1002709 [Google Scholar]
  112. Vacic V, Iakoucheva LM. 112.  2012. Disease mutations in disordered regions—exception to the rule?. Mol. Biosyst. 8:27–32 [Google Scholar]
  113. Radivojac P, Vacic V, Haynes C, Cocklin RR, Mohan A. 113.  et al. 2010. Identification, analysis, and prediction of protein ubiquitination sites. Proteins 78:365–80 [Google Scholar]
  114. Gao J, Thelen JJ, Dunker AK, Xu D. 114.  2010. Musite, a tool for global prediction of general and kinase-specific phosphorylation sites. Mol. Cell Proteomics 9:2586–600 [Google Scholar]
  115. Allers T.115.  2010. Overexpression and purification of halophilic proteins in Haloferax volcanii. Bioeng. Bugs 1:288–90 [Google Scholar]
  116. Fukuchi S, Hosoda K, Homma K, Gojobori T, Nishikawa K. 116.  2011. Binary classification of protein molecules into intrinsically disordered and ordered segments. BMC Struct. Biol. 11:29 [Google Scholar]
  117. Oates ME, Romero P, Ishida T, Ghalwash M, Mizianty MJ. 117.  et al. 2013. D2P2: database of disordered protein predictions. Nucleic Acids Res. 41:D508–16 [Google Scholar]
  118. Pentony MM, Jones DT. 118.  2010. Modularity of intrinsic disorder in the human proteome. Proteins 78:212–21 [Google Scholar]
  119. Sigler PB.119.  1988. Transcriptional activation, acid blobs and negative noodles. Nature 333:210–12 [Google Scholar]
  120. Liu J, Perumal NB, Oldfield CJ, Su EW, Uversky VN, Dunker AK. 120.  2006. Intrinsic disorder in transcription factors. Biochemistry 45:6873–88 [Google Scholar]
  121. Minezaki Y, Homma K, Kinjo AR, Nishikawa K. 121.  2006. Human transcription factors contain a high fraction of intrinsically disordered regions essential for transcriptional regulation. J. Mol. Biol. 359:1137–49 [Google Scholar]
  122. Uversky VN, Dunker AK. 122.  2012. Methods in Molecular Biology 895 Intrinsically Disordered Protein Analysis. 1 New York: Humana
  123. Uversky VN, Dunker AK. 123.  2012. Methods in Molecular Biology 896 Intrinsically Disordered Protein Analysis. 2 New York: Humana
  124. Fontana A, Zambonin M, Polverino de Laureto P, De Filippis V, Clementi A, Scaramella E. 124.  1997. Probing the conformational state of apomyoglobin by limited proteolysis. J. Mol. Biol. 266:223–30 [Google Scholar]
  125. Iakoucheva LM, Kimzey AL, Masselon CD, Bruce JE, Garner EC. 125.  et al. 2001. Identification of intrinsic order and disorder in the DNA repair protein XPA. Protein Sci. 10:560–71 [Google Scholar]
  126. Liu Y, Matthews KS, Bondos SE. 126.  2008. Multiple intrinsically disordered sequences alter DNA binding by the homeodomain of the Drosophila Hox protein ultrabithorax. J. Biol. Chem. 283:20874–87 [Google Scholar]
  127. Johnson DE, Xue B, Sickmeier MD, Meng J, Cortese MS. 127.  et al. 2012. High-throughput characterization of intrinsic disorder in proteins from the protein structure initiative. J. Struct. Biol. 180:201–15 [Google Scholar]
  128. Hubbell WL, Gross A, Langen R, Lietzow MA. 128.  1998. Recent advances in site-directed spin labeling of proteins. Curr. Opin. Struct. Biol. 8:649–56 [Google Scholar]
  129. Langen R, Cai K, Altenbach C, Khorana HG, Hubbell WL. 129.  1999. Structural features of the C-terminal domain of bovine rhodopsin: a site-directed spin-labeling study. Biochemistry 38:7918–24 [Google Scholar]
  130. Belle V, Rouger S, Costanzo S, Liquière E, Strancar J. 130.  et al. 2008. Mapping α-helical induced folding within the intrinsically disordered C-terminal domain of the measles virus nucleoprotein by site-directed spin-labeling EPR spectroscopy. Proteins 73:973–88 [Google Scholar]
  131. Receveur-Brechot V, Durand D. 131.  2012. How random are intrinsically disordered proteins? A small angle scattering perspective. Curr. Protein Pept. Sci. 13:55–75 [Google Scholar]
  132. Hura GL, Budworth H, Dyer KN, Rambo RP, Hammel M. 132.  et al. 2013. Comprehensive macromolecular conformations mapped by quantitative SAXS analyses. Nat. Methods 10:453–54 [Google Scholar]
  133. Hegde ML, Tsutakawa SE, Hegde PM, Holthauzen LMF, Li J. 133.  et al. 2013. The disordered C-terminal domain of human DNA glycosylase NEIL1 contributes to its stability via intramolecular interactions. J. Mol. Biol. 425:2359–71 [Google Scholar]
  134. Varadi M, Kosol S, Lebrun P, Valentini E, Blackledge M. 134.  et al. 2014. pE-DB: the database of structural ensembles of intrinsically disordered and denatured proteins. Nucleic Acids Res 42:D326–35 [Google Scholar]
  135. Cortese MS, Uversky VN, Dunker AK. 135.  2008. Intrinsic disorder in scaffold proteins: getting more from less. Prog. Biophys. Mol. Biol. 98:85–106 [Google Scholar]
  136. Buday L, Tompa P. 136.  2010. Functional classification of scaffold proteins and related molecules. FEBS J. 277:4348–55 [Google Scholar]
  137. Xue B, Dunker AK, Uversky VN. 137.  2012. The roles of intrinsic disorder in orchestrating the Wnt pathway. J. Biomol. Struct. Dyn. 29:843–61 [Google Scholar]
  138. Noutsou M, Duarte AMS, Anvarian Z, Didenko T, Minde DP. 138.  et al. 2011. Critical scaffolding regions of the tumor suppressor axin1 are natively unfolded. J. Mol. Biol. 405:773–86 [Google Scholar]
  139. Kuriyan J, Eisenberg D. 139.  2007. The origin of protein interactions and allostery in colocalization. Nature 450:983–90 [Google Scholar]
  140. Xue B, Romero PR, Noutsou M, Maurice MM, Rüdiger SGD. 140.  et al. 2013. Stochastic machines as a colocalization mechanism for scaffold protein function. FEBS Lett. 587:1587–91 [Google Scholar]
  141. Frye JJ, Brown NG, Petzold G, Watson ER, Grace CRR. 141.  et al. 2013. Electron microscopy structure of human APC/CCDH1–EMI1 reveals multimodal mechanism of E3 ligase shutdown. Nat. Struct. Mol. Biol. 20:827–35 [Google Scholar]
  142. Dunker AK, Garner E, Guilliot S, Romero P, Albrecht K. 142.  et al. 1998. Protein disorder and the evolution of molecular recognition: theory, predictions and observations. Pac. Symp. Biocomput. 3:473–84 [Google Scholar]
  143. Dunker AK, Brown CJ, Lawson JD, Iakoucheva LM, Obradović Z. 143.  2002. Intrinsic disorder and protein function. Biochemistry 41:6573–82 [Google Scholar]
  144. Dyson HJ, Wright PE. 144.  2005. Intrinsically unstructured proteins and their functions. Nat. Rev. Mol. Cell Biol. 6:197–208 [Google Scholar]
  145. Xie H, Vucetic S, Iakoucheva LM, Oldfield CJ, Dunker AK. 145.  et al. 2007. Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions. J. Proteome Res. 6:1882–98 [Google Scholar]
  146. Vucetic S, Xie H, Iakoucheva LM, Oldfield CJ, Dunker AK. 146.  et al. 2007. Functional anthology of intrinsic disorder. 2. Cellular components, domains, technical terms, developmental processes, and coding sequence diversities correlated with long disordered regions. J. Proteome Res. 6:1899–916 [Google Scholar]
  147. Xie H, Vucetic S, Iakoucheva LM, Oldfield CJ, Dunker AK. 147.  et al. 2007. Functional anthology of intrinsic disorder. 3. Ligands, post-translational modifications, and diseases associated with intrinsically disordered proteins. J. Proteome Res. 6:1917–32 [Google Scholar]
  148. Fersht AR, Knill-Jones JW, Bedouelle H, Winter G. 148.  1988. Reconstruction by site-directed mutagenesis of the transition state for the activation of tyrosine by the tyrosyl-tRNA synthetase: A mobile loop envelopes the transition state in an induced-fit mechanism. Biochemistry 27:1581–87 [Google Scholar]
  149. McElheny D, Schnell JR, Lansing JC, Dyson HJ, Wright PE. 149.  2005. Defining the role of active-site loop fluctuations in dihydrofolate reductase catalysis. Proc. Natl. Acad. Sci. USA 102:5032–37 [Google Scholar]
  150. Radivojac P, Clark WT, Oron TR, Schnoes AM, Wittkop T. 150.  et al. 2013. A large-scale evaluation of computational protein function prediction. Nat. Methods 10:221–27 [Google Scholar]
  151. Cozzetto D, Jones DT. 151.  2013. The contribution of intrinsic disorder prediction to the elucidation of protein function. Curr. Opin. Struct. Biol. 23:467–72 [Google Scholar]
  152. Sickmeier M, Hamilton JA, LeGall T, Vacic V, Cortese MS. 152.  et al. 2007. DisProt: the database of disordered proteins. Nucleic Acids Res. 35:D786–93 [Google Scholar]
  153. Fukuchi S, Sakamoto S, Nobe Y, Murakami SD, Amemiya T. 153.  et al. 2012. IDEAL: intrinsically disordered proteins with extensive annotations and literature. Nucleic Acids Res. 40:D507–11 [Google Scholar]
  154. Di Domenico T, Walsh I, Martin AJ, Tosatto SC. 154.  2012. MobiDB: a comprehensive database of intrinsic protein disorder annotations. Bioinformatics 28:2080–81 [Google Scholar]
  155. Singh J, Whitwill S, Lacroix G, Douglas J, Dubuc E. 155.  et al. 2009. The use of group 3 LEA proteins as fusion partners in facilitating recombinant expression of recalcitrant proteins in E. coli. Protein Expr. Purif. 67:15–22 [Google Scholar]
  156. Santner AA, Croy CH, Vasanwala FH, Uversky VN, Van Y-YJ, Dunker AK. 156.  2012. Sweeping away protein aggregation with entropic bristles: Intrinsically disordered protein fusions enhance soluble expression. Biochemistry 51:7250–62 [Google Scholar]
  157. Janin J, Sternberg MJE. 157.  2013. Protein flexibility, not disorder, is intrinsic to molecular recognition. F1000 Biol. Rep. 5:2 [Google Scholar]
  158. Tompa P, Prilusky J, Silman I, Sussman JL. 158.  2008. Structural disorder serves as a weak signal for intracellular protein degradation. Proteins 71:903–9 [Google Scholar]
  159. Tsvetkov P, Reuven N, Shaul Y. 159.  2009. The nanny model for IDPs. Nat. Chem. Biol. 5:778–81 [Google Scholar]
  160. Singh GP, Ganapathi M, Sandhu KS, Dash D. 160.  2006. Intrinsic unstructuredness and abundance of pest motifs in eukaryotic proteomes. Proteins 62:309–15 [Google Scholar]
  161. Sandhu KS, Dash D. 161.  2006. Conformational flexibility may explain multiple cellular roles of pest motifs. Proteins 63:727–32 [Google Scholar]
  162. Garner E, Romero P, Dunker AK, Brown C, Obradović Z. 162.  1999. Predicting binding regions within disordered proteins. Workshop Genome Inform. 10:41–50 [Google Scholar]
  163. Cheng Y, Oldfield CJ, Meng J, Romero P, Uversky VN, Dunker AK. 163.  2007. Mining α-helix-forming molecular recognition features with cross species sequence alignments. Biochemistry 46:13468–77 [Google Scholar]
  164. Vacic V, Oldfield CJ, Mohan A, Radivojac P, Cortese MS. 164.  et al. 2007. Characterization of molecular recognition features, morfs, and their binding partners. J. Proteome Res. 6:2351–66 [Google Scholar]
  165. Wong ETC, Na D, Gsponer J. 165.  2013. On the importance of polar interactions for complexes containing intrinsically disordered proteins. PLoS Comput. Biol. 9:e1003192 [Google Scholar]
  166. Gosselin P, Oulhen N, Jam M, Ronzca J, Cormier P. 166.  et al. 2011. The translational repressor 4E-BP called to order by eIF4E: new structural insights by SAXS. Nucleic Acids Res. 39:3496–503 [Google Scholar]
  167. Le Gall T, Romero PR, Cortese MS, Uversky VN, Dunker AK. 167.  2007. Intrinsic disorder in the Protein Data Bank. J. Biomol. Struct. Dyn. 24:325–42 [Google Scholar]
  168. Zhang Y, Stec B, Godzik A. 168.  2007. Between order and disorder in protein structures: analysis of “dual personality” fragments in proteins. Structure 15:1141–47 [Google Scholar]
  169. Dunker AK.169.  2007. Another window into disordered protein function. Structure 15:1026–28 [Google Scholar]
  170. Dosztányi Z, Mészáros B, Simon I. 170.  2009. ANCHOR: web server for predicting protein binding regions in disordered proteins. Bioinformatics 25:2745–46 [Google Scholar]
  171. Disfani FM, Hsu W-L, Mizianty MJ, Oldfield CJ, Xue B. 171.  et al. 2012. MoRFpred, a computational tool for sequence-based prediction and characterization of short disorder-to-order transitioning binding regions in proteins. Bioinformatics 28:i75–83 [Google Scholar]
  172. Obenauer JC, Cantley LC, Yaffe MB. 172.  2003. Scansite 2.0: proteome-wide prediction of cell signaling interactions using short sequence motifs. Nucleic Acids Res. 31:3635–41 [Google Scholar]
  173. Puntervoll P, Linding R, Gemünd C, Chabanis-Davidson S, Mattingsdal M. 173.  et al. 2003. ELM server: a new resource for investigating short functional sites in modular eukaryotic proteins. Nucleic Acids Res. 31:3625–30 [Google Scholar]
  174. Davey NE, Edwards RJ, Shields DC. 174.  2007. The SLiMDisc server: short, linear motif discovery in proteins. Nucleic Acids Res. 35:W455–59 [Google Scholar]
  175. Mi T, Merlin JC, Deverasetty S, Gryk MR, Bill TJ. 175.  et al. 2012. Minimotif Miner 3.0: database expansion and significantly improved reduction of false-positive predictions from consensus sequences. Nucleic Acids Res. 40:D252–60 [Google Scholar]
  176. Mészáros B, Dosztányi Z, Simon I. 176.  2012. Disordered binding regions and linear motifs—bridging the gap between two models of molecular recognition. PLoS ONE 7:e46829 [Google Scholar]
  177. Sargeant DP, Gryk MR, Maciejewski MW, Thapar V, Kundeti V. 177.  et al. 2012. Secondary structure, a missing component of sequence-based Minimotif definitions. PLoS ONE 7:e49957 [Google Scholar]
  178. Gunasekaran K, Tsai C-J, Nussinov R. 178.  2004. Analysis of ordered and disordered protein complexes reveals structural features discriminating between stable and unstable monomers. J. Mol. Biol. 341:1327–41 [Google Scholar]
  179. Oldfield CJ, Meng J, Yang JY, Yang MQ, Uversky VN, Dunker AK. 179.  2008. Flexible nets: disorder and induced fit in the associations of p53 and 14-3-3 with their partners. BMC Genomics 9:Suppl. 1):S1 [Google Scholar]
  180. Peng Z, Oldfield CJ, Xue B, Mizianty MJ, Dunker AK. 180.  et al. 2013. A creature with a hundred waggly tails: intrinsically disordered proteins in the ribosome. Cell Mol. Life Sci. 711477–504
  181. Fuxreiter M, Simon I, Friedrich P, Tompa P. 181.  2004. Preformed structural elements feature in partner recognition by intrinsically unstructured proteins. J. Mol. Biol. 338:1015–26 [Google Scholar]
  182. Burgen AS, Roberts GC, Feeney J. 182.  1975. Binding of flexible ligands to macromolecules. Nature 253:753–55 [Google Scholar]
  183. Koshland DE Jr. 183.  1959. Enzyme flexibility and enzyme action. J. Cell Comp. Physiol. 54:245–58 [Google Scholar]
  184. Spolar RS, Record MT Jr. 184.  1994. Coupling of local folding to site-specific binding of proteins to DNA. Science 263:777–84 [Google Scholar]
  185. Espinoza-Fonseca LM.185.  2009. Reconciling binding mechanisms of intrinsically disordered proteins. Biochem. Biophys. Res. Commun. 382:479–82 [Google Scholar]
  186. Sugase K, Dyson HJ, Wright PE. 186.  2007. Mechanism of coupled folding and binding of an intrinsically disordered protein. Nature 447:1021–25 [Google Scholar]
  187. Choy MS, Page R, Peti W. 187.  2012. Regulation of protein phosphatase 1 by intrinsically disordered proteins. Biochem. Soc. Trans. 40:969–74 [Google Scholar]
  188. Drobnak I, De Jonge N, Haesaerts S, Vesnaver G, Loris R, Lah J. 188.  2013. Energetic basis of uncoupling folding from binding for an intrinsically disordered protein. J. Am. Chem. Soc. 135:1288–94 [Google Scholar]
  189. Gruet A, Dosnon M, Vassena A, Lombard V, Gerlier D. 189.  et al. 2013. Dissecting partner recognition by an intrinsically disordered protein using descriptive random mutagenesis. J. Mol. Biol. 425:3495–509 [Google Scholar]
  190. Shammas SL, Rogers JM, Hill SA, Clarke J. 190.  2012. Slow, reversible, coupled folding and binding of the spectrin tetramerization domain. Biophys. J. 103:2203–14 [Google Scholar]
  191. Shammas SL, Travis AJ, Clarke J. 191.  2013. Remarkably fast coupled folding and binding of the intrinsically disordered transactivation domain of cMyb to CBP KIX. J. Phys. Chem. B 117:13346–56 [Google Scholar]
  192. Shoemaker BA, Portman JJ, Wolynes PG. 192.  2000. Speeding molecular recognition by using the folding funnel: the fly-casting mechanism. Proc. Natl. Acad. Sci. USA 97:8868–73 [Google Scholar]
  193. Zhou H-X, Bates PA. 193.  2013. Modeling protein association mechanisms and kinetics. Curr. Opin. Struct. Biol. 23:887–93 [Google Scholar]
  194. Hasty J, Collins JJ. 194.  2001. Protein interactions. Unspinning the web. Nature 411:30–31 [Google Scholar]
  195. Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN. 195.  2005. Flexible nets. The roles of intrinsic disorder in protein interaction networks. FEBS J. 272:5129–48 [Google Scholar]
  196. Uversky VN, Dunker AK. 196.  2010. Understanding protein non-folding. Biochim. Biophys. Acta 1804:1231–64 [Google Scholar]
  197. Hsu WL.197.  2013. Mechanisms of binding diversity in protein disorder: molecular recognition features mediating protein interaction networks PhD thesis, Indiana Univ., Indianapolis 100
  198. Buljan M, Chalancon G, Dunker AK, Bateman A, Balaji S. 198.  et al. 2013. Alternative splicing of intrinsically disordered regions and rewiring of protein interactions. Curr. Opin. Struct. Biol. 23:443–50 [Google Scholar]
  199. Colak R, Kim T, Michaut M, Sun M, Irimia M. 199.  et al. 2013. Distinct types of disorder in the human proteome: functional implications for alternative splicing. PLoS Comput. Biol. 9:e1003030 [Google Scholar]
  200. Ellis JD, Barrios-Rodiles M, Colak R, Irimia M, Kim T. 200.  et al. 2012. Tissue-specific alternative splicing remodels protein–protein interaction networks. Mol. Cell 46:884–92 [Google Scholar]
  201. Demarest SJ, Martinez-Yamout M, Chung J, Chen H, Xu W. 201.  et al. 2002. Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators. Nature 415:549–53 [Google Scholar]
  202. Marchler-Bauer A, Panchenko AR, Shoemaker BA, Thiessen PA, Geer LY, Bryant SH. 202.  2002. CDD: a database of conserved domain alignments with links to domain three-dimensional structure. Nucleic Acids Res. 30:281–83 [Google Scholar]
  203. Tompa P, Fuxreiter M, Oldfield CJ, Simon I, Dunker AK, Uversky VN. 203.  2009. Close encounters of the third kind: disordered domains and the interactions of proteins. Bioessays 31:328–35 [Google Scholar]
  204. Punta M, Coggill PC, Eberhardt RY, Mistry J, Tate J. 204.  et al. 2012. The Pfam protein families database. Nucleic Acids Res. 40:D290–301 [Google Scholar]
  205. Williams RW, Xue B, Uversky VN, Dunker AK. 205.  2013. Distribution and cluster analysis of predicted disordered proteins in Pfam domains. Intrinsically Disord. Proteins 1:e25724 [Google Scholar]
  206. Galea CA, Nourse A, Wang Y, Sivakolundu SG, Heller WT, Kriwacki RW. 206.  2008. Role of intrinsic flexibility in signal transduction mediated by the cell cycle regulator, p27kip1. J. Mol. Biol. 376:827–38 [Google Scholar]
  207. Dunker AK, Uversky VN. 207.  2008. Signal transduction via unstructured protein conduits. Nat. Chem. Biol. 4:229–30 [Google Scholar]
  208. Follis AV, Galea CA, Kriwacki RW. 208.  2012. Intrinsic protein flexibility in regulation of cell proliferation: advantages for signaling and opportunities for novel therapeutics. Adv. Exp. Med. Biol. 725:27–49 [Google Scholar]
  209. Mohan A, Oldfield CJ, Radivojac P, Vacic V, Cortese MS. 209.  et al. 2006. Analysis of molecular recognition features (MoRFs). J. Mol. Biol. 362:1043–59 [Google Scholar]
  210. Tompa P, Fuxreiter M. 210.  2008. Fuzzy complexes: polymorphism and structural disorder in protein–protein interactions. Trends Biochem. Sci. 33:2–8 [Google Scholar]
  211. Marcotrigiano J, Gingras AC, Sonenberg N, Burley SK. 211.  1999. Cap-dependent translation initiation in eukaryotes is regulated by a molecular mimic of eIF4G. Mol. Cell 3:707–16 [Google Scholar]
  212. Nash P, Tang X, Orlicky S, Chen Q, Gertler FB. 212.  et al. 2001. Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication. Nature 414:514–21 [Google Scholar]
  213. Borg M, Mittag T, Pawson T, Tyers M, Forman-Kay JD, Chan HS. 213.  2007. Polyelectrostatic interactions of disordered ligands suggest a physical basis for ultrasensitivity. Proc. Natl. Acad. Sci. USA 104:9650–55 [Google Scholar]
  214. Schulz GE.214.  1979. Nucleotide binding proteins. Moledular Mechanisms of Biological Recognition M Balaban 79–94 Amsterdam: Elsevier/North-Holland [Google Scholar]
  215. Nadassy K, Wodak SJ, Janin J. 215.  1999. Structural features of protein–nucleic acid recognition sites. Biochemistry 38:1999–2017 [Google Scholar]
  216. Vuzman D, Levy Y. 216.  2012. Intrinsically disordered regions as affinity tuners in protein–DNA interactions. Mol. Biosyst. 8:47–57 [Google Scholar]
  217. Passner JM, Ryoo HD, Shen L, Mann RS, Aggarwal AK. 217.  1999. Structure of a DNA-bound ultrabithorax-extradenticle homeodomain complex. Nature 397:714–19 [Google Scholar]
  218. Wahl MC, Will CL, Lührmann R. 218.  2009. The spliceosome: design principles of a dynamic RNP machine. Cell 136:701–18 [Google Scholar]
  219. Moore PB.219.  2012. How should we think about the ribosome?. Annu. Rev. Biophys. 41:1–19 [Google Scholar]
  220. Lecompte O, Ripp R, Thierry J-C, Moras D, Poch O. 220.  2002. Comparative analysis of ribosomal proteins in complete genomes: an example of reductive evolution at the domain scale. Nucleic Acids Res. 30:5382–90 [Google Scholar]
  221. Timsit Y, Acosta Z, Allemand F, Chiaruttini C, Springer M. 221.  2009. The role of disordered ribosomal protein extensions in the early steps of eubacterial 50S ribosomal subunit assembly. Int. J. Mol. Sci. 10:817–34 [Google Scholar]
  222. Coelho Ribeiro MdL, Espinosa J, Islam S, Martinez O, Thanki JJ. 222.  et al. 2013. Malleable ribonucleoprotein machine: protein intrinsic disorder in the Saccharomyces cerevisiae spliceosome. PeerJ 1:e2 [Google Scholar]
  223. Monod J, Wyman J, Changeux JP. 223.  1965. On the nature of allosteric transitions: a plausible model. J. Mol. Biol. 12:88–118 [Google Scholar]
  224. Koshland DE Jr, Némethy G, Filmer D. 224.  1966. Comparison of experimental binding data and theoretical models in proteins containing subunits. Biochemistry 5:365–85 [Google Scholar]
  225. Hilser VJ.225.  2010. Biochemistry. An ensemble view of allostery. Science 327:653–54 [Google Scholar]
  226. Beckett D.226.  2009. Regulating transcription regulators via allostery and flexibility. Proc. Natl. Acad. Sci. USA 106:22035–36 [Google Scholar]
  227. Motlagh HN, Hilser VJ. 227.  2012. Agonism/antagonism switching in allosteric ensembles. Proc. Natl. Acad. Sci. USA 109:4134–39 [Google Scholar]
  228. Kumar R, McEwan IJ. 228.  2012. Allosteric modulators of steroid hormone receptors: structural dynamics and gene regulation. Endocr. Rev. 33:271–99 [Google Scholar]
  229. Ferreon ACM, Ferreon JC, Wright PE, Deniz AA. 229.  2013. Modulation of allostery by protein intrinsic disorder. Nature 498:390–94 [Google Scholar]
  230. Ivanyi-Nagy R, Davidovic L, Khandjian EW, Darlix J-L. 230.  2005. Disordered RNA chaperone proteins: from functions to disease. Cell Mol. Life Sci. 62:1409–17 [Google Scholar]
  231. Tompa P, Csermely P. 231.  2004. The role of structural disorder in the function of RNA and protein chaperones. FASEB J. 18:1169–75 [Google Scholar]
  232. Shewmaker F, Kerner MJ, Hayer-Hartl M, Klein G, Georgopoulos C, Landry SJ. 232.  2004. A mobile loop order-disorder transition modulates the speed of chaperonin cycling. Protein Sci. 13:2139–48 [Google Scholar]
  233. Tompa P, Kovacs D. 233.  2010. Intrinsically disordered chaperones in plants and animals. Biochem. Cell Biol. 88:167–74 [Google Scholar]
  234. Thorn DC, Ecroyd H, Sunde M, Poon S, Carver JA. 234.  2008. Amyloid fibril formation by bovine milk αS2-casein occurs under physiological conditions yet is prevented by its natural counterpart, αS1-casein. Biochemistry 47:3926–36 [Google Scholar]
  235. Bordo D, Argos P. 235.  1990. Evolution of protein cores. Constraints in point mutations as observed in globin tertiary structures. J. Mol. Biol. 211:975–88 [Google Scholar]
  236. Jernigan RL, Kloczkowski A. 236.  2007. Packing regularities in biological structures relate to their dynamics. Methods Mol. Biol. 350:251–76 [Google Scholar]
  237. Chen JW, Romero P, Uversky VN, Dunker AK. 237.  2006. Conservation of intrinsic disorder in protein domains and families. I. A database of conserved predicted disordered regions. J. Proteome Res. 5:879–87 [Google Scholar]
  238. Chen JW, Romero P, Uversky VN, Dunker AK. 238.  2006. Conservation of intrinsic disorder in protein domains and families. II. Functions of conserved disorder. J. Proteome Res. 5:888–98 [Google Scholar]
  239. Bellay J, Han S, Michaut M, Kim T, Costanzo M. 239.  et al. 2011. Bringing order to protein disorder through comparative genomics and genetic interactions. Genome Biol. 12:R14 [Google Scholar]
  240. Buljan M, Chalancon G, Eustermann S, Wagner GP, Fuxreiter M. 240.  et al. 2012. Tissue-specific splicing of disordered segments that embed binding motifs rewires protein interaction networks. Mol. Cell 46:871–83 [Google Scholar]
  241. Daughdrill GW, Narayanaswami P, Gilmore SH, Belczyk A, Brown CJ. 241.  2007. Dynamic behavior of an intrinsically unstructured linker domain is conserved in the face of negligible amino acid sequence conservation. J. Mol. Evol. 65:277–88 [Google Scholar]
  242. Brown CJ, Johnson AK, Daughdrill GW. 242.  2010. Comparing models of evolution for ordered and disordered proteins. Mol. Biol. Evol. 27:609–21 [Google Scholar]
  243. Mosca R, Pache RA, Aloy P. 243.  2012. The role of structural disorder in the rewiring of protein interactions through evolution. Mol. Cell Proteomics 11:M111.014969 [Google Scholar]
  244. Barbosa-Morais NL, Irimia M, Pan Q, Xiong HY, Gueroussov S. 244.  et al. 2012. The evolutionary landscape of alternative splicing in vertebrate species. Science 338:1587–93 [Google Scholar]
  245. Merkin J, Russell C, Chen P, Burge CB. 245.  2012. Evolutionary dynamics of gene and isoform regulation in mammalian tissues. Science 338:1593–99 [Google Scholar]
  246. Van Roey K, Dinkel H, Weatheritt RJ, Gibson TJ, Davey NE. 246.  2013. The switches.elm resource: a compendium of conditional regulatory interaction interfaces. Sci. Signal. 6:rs7 [Google Scholar]
  247. Xue B, Brown CJ, Dunker AK, Uversky VN. 247.  2013. Intrinsically disordered regions of p53 family are highly diversified in evolution. Biochim. Biophys. Acta 1834:725–38 [Google Scholar]
  248. Schaefer C, Schlessinger A, Rost B. 248.  2010. Protein secondary structure appears to be robust under in silico evolution while protein disorder appears not to be. Bioinformatics 26:625–31 [Google Scholar]
  249. Schlessinger A, Schaefer C, Vicedo E, Schmidberger M, Punta M, Rost B. 249.  2011. Protein disorder—a breakthrough invention of evolution?. Curr. Opin. Struct. Biol. 21:412–18 [Google Scholar]
  250. Vavouri T, Semple JI, Garcia-Verdugo R, Lehner B. 250.  2009. Intrinsic protein disorder and interaction promiscuity are widely associated with dosage sensitivity. Cell 138:198–208 [Google Scholar]
  251. Gsponer J, Futschik ME, Teichmann SA, Babu MM. 251.  2008. Tight regulation of unstructured proteins: from transcript synthesis to protein degradation. Science 322:1365–68 [Google Scholar]
  252. Uversky VN, Dunker AK. 252.  2008. Biochemistry: controlled chaos. Science 322:1340–41 [Google Scholar]
  253. Tompa P, Szász C, Buday L. 253.  2005. Structural disorder throws new light on moonlighting. Trends Biochem. Sci. 30:484–89 [Google Scholar]
  254. Davey NE, Travé G, Gibson TJ. 254.  2011. How viruses hijack cell regulation. Trends Biochem. Sci. 36:159–69 [Google Scholar]
  255. Mahani A, Henricksson J, Wright APH. 255.  2013. Origins of myc proteins—using intrinsic disorder predictors to trace distant relatives. PLoS ONE 8:e75057 [Google Scholar]
  256. Mark W-Y, Liao JCC, Lu Y, Ayed A, Laister R. 256.  et al. 2005. Characterization of segments from the central region of BRCA1: an intrinsically disordered scaffold for multiple protein–protein and protein–DNA interactions?. J. Mol. Biol. 345:275–87 [Google Scholar]
  257. Bondos SE, Hsiao H-C. 257.  2012. Roles for intrinsic disorder and fuzziness in generating context-specific function in ultrabithorax, a Hox transcription factor. Adv. Exp. Med. Biol. 725:86–105 [Google Scholar]
  258. Voet D, Voet JG, Pratt CW. 258.  2012. Fundamentals of Biochemistry: Life at the Molecular Level. Hoboken, NJ: Wiley. 1200 pp. 4th ed.
  259. Pratt CW, Cornely K. 259.  2013. Essential Biochemistry.. Hoboken, NJ: Wiley 744 pp. 3rd ed.
  260. McKee T, McKee JR.260.  2014. Biochemistry: The Molecular Basis of Life. New York: Oxford Univ. Press. 944 pp. 5th ed.
  261. Tymoczko JL, Berg JM, Stryer L.261.  2011. Biochemistry: A Short Course. New York: Freeman. 800 pp. 2nd ed.
  262. Voet D, Voet JG.262.  2010. Biochemistry. Hoboken, NJ: Wiley. 1428 pp. 4th ed.
  263. Nelson DL, Cox MM. 263.  2012. Lehninger Principles of Biochemistry.. New York: Freeman. 1100 pp. 6th ed.

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error