Journal of Biomedicine and Biotechnology
Volume 2010 (2010), Article ID 568068, 14 pages
doi:10.1155/2010/568068
Review Article

The Mysterious Unfoldome: Structureless, Underappreciated, Yet Vital Part of Any Given Proteome

1Institute for Intrinsically Disordered Protein Research, The Center for Computational Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
2Institute for Biological Instrumentation, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia
3Molecular Kinetics Inc., Indianapolis, IN 46268, USA

Received 22 July 2009; Accepted 10 September 2009

Academic Editor: Beatrix M. Ueberheide

Copyright © 2010 Vladimir N. Uversky. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. E. Fischer, “Einfluss der configuration auf die wirkung der enzyme,” Berichte der Deutschen Chemischen Gesellschaft, vol. 27, no. 3, pp. 2985–2993, 1894. View at Publisher · View at Google Scholar
  2. R. U. Lemieux and U. Spohr, “How Emil Fischer was led to the lock and key concept for enzyme specificity,” Advances in Carbohydrate Chemistry and Biochemistry, vol. 50, pp. 1–20, 1994. View at Scopus
  3. C. M. Dobson, “Protein misfolding, evolution and disease,” Trends in Biochemical Sciences, vol. 24, no. 9, pp. 329–332, 1999. View at Publisher · View at Google Scholar · View at Scopus
  4. A. K. Dunker, C. J. Oldfield, J. Meng, et al., “The unfoldomics decade: an update on intrinsically disordered proteins,” BMC Genomics, vol. 9, supplement 2, article S1, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  5. A. K. Dunker, C. J. Brown, J. D. Lawson, L. M. Iakoucheva, and Z. Obradović, “Intrinsic disorder and protein function,” Biochemistry, vol. 41, no. 21, pp. 6573–6582, 2002. View at Publisher · View at Google Scholar · View at Scopus
  6. A. K. Dunker, C. J. Brown, and Z. Obradović, “Identification and functions of usefully disordered proteins,” Advances in Protein Chemistry, vol. 62, pp. 25–49, 2002. View at Publisher · View at Google Scholar · View at Scopus
  7. A. K. Dunker, M. S. Cortese, P. Romero, L. M. Iakoucheva, and V. N. Uversky, “Flexible nets: the roles of intrinsic disorder in protein interaction networks,” FEBS Journal, vol. 272, no. 20, pp. 5129–5148, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  8. A. K. Dunker, J. D. Lawson, C. J. Brown, et al., “Intrinsically disordered protein,” Journal of Molecular Graphics and Modelling, vol. 19, no. 1, pp. 26–59, 2001. View at Publisher · View at Google Scholar · View at Scopus
  9. A. K. Dunker and Z. Obradović, “The protein trinity—linking function and disorder,” Nature Biotechnology, vol. 19, no. 9, pp. 805–806, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  10. P. Radivojac, L. M. Iakoucheva, C. J. Oldfield, Z. Obradović, V. N. Uversky, and A. K. Dunker, “Intrinsic disorder and functional proteomics,” Biophysical Journal, vol. 92, no. 5, pp. 1439–1456, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  11. A. K. Dunker, I. Silman, V. N. Uversky, and J. L. Sussman, “Function and structure of inherently disordered proteins,” Current Opinion in Structural Biology, vol. 18, no. 6, pp. 756–764, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  12. A. K. Dunker and V. N. Uversky, “Signal transduction via unstructured protein conduits,” Nature Chemical Biology, vol. 4, no. 4, pp. 229–230, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  13. S. Vucetic, H. Xie, L. M. Iakoucheva, et al., “Functional anthology of intrinsic disorder. 2. Cellular components, domains, technical terms, developmental processes, and coding sequence diversities correlated with long disordered regions,” Journal of Proteome Research, vol. 6, no. 5, pp. 1899–1916, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  14. H. Xie, S. Vucetic, L. M. Iakoucheva, et al., “Functional anthology of intrinsic disorder. 3. Ligands, post-translational modifications, and diseases associated with intrinsically disordered proteins,” Journal of Proteome Research, vol. 6, no. 5, pp. 1917–1932, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  15. H. Xie, S. Vucetic, L. M. Iakoucheva, et al., “Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions,” Journal of Proteome Research, vol. 6, no. 5, pp. 1882–1898, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. M. S. Cortese, V. N. Uversky, and A. Keith Dunker, “Intrinsic disorder in scaffold proteins: getting more from less,” Progress in Biophysics and Molecular Biology, vol. 98, no. 1, pp. 85–106, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  17. R. B. Russell and T. J. Gibson, “A careful disorderliness in the proteome: sites for interaction and targets for future therapies,” FEBS Letters, vol. 582, no. 8, pp. 1271–1275, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  18. C. J. Oldfield, J. Meng, J. Y. Yang, M. Q. Qu, V. N. Uversky, and A. K. Dunker, “Flexible nets: disorder and induced fit in the associations of p53 and 14-3-3 with their partners,” BMC Genomics, vol. 9, supplement 1, article S1, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  19. P. Tompa and P. Csermely, “The role of structural disorder in the function of RNA and protein chaperones,” FASEB Journal, vol. 18, no. 11, pp. 1169–1175, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  20. V. N. Uversky, C. J. Oldfield, and A. K. Dunker, “Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling,” Journal of Molecular Recognition, vol. 18, no. 5, pp. 343–384, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  21. P. E. Wright and H. J. Dyson, “Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm,” Journal of Molecular Biology, vol. 293, no. 2, pp. 321–331, 1999. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  22. P. Tompa, “Intrinsically unstructured proteins,” Trends in Biochemical Sciences, vol. 27, no. 10, pp. 527–533, 2002. View at Publisher · View at Google Scholar · View at Scopus
  23. V. N. Uversky, “Natively unfolded proteins: a point where biology waits for physics,” Protein Science, vol. 11, no. 4, pp. 739–756, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  24. H. J. Dyson and P. E. Wright, “Intrinsically unstructured proteins and their functions,” Nature Reviews Molecular Cell Biology, vol. 6, no. 3, pp. 197–208, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  25. L. M. Iakoucheva, C. J. Brown, J. D. Lawson, Z. Obradović, and A. K. Dunker, “Intrinsic disorder in cell-signaling and cancer-associated proteins,” Journal of Molecular Biology, vol. 323, no. 3, pp. 573–584, 2002. View at Publisher · View at Google Scholar · View at Scopus
  26. A. K. Dunker, I. Silman, V. N. Uversky, and J. L. Sussman, “Function and structure of inherently disordered proteins,” Current Opinion in Structural Biology, vol. 18, no. 6, pp. 756–764, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  27. P. Tompa, “The interplay between structure and function in intrinsically unstructured proteins,” FEBS Letters, vol. 579, no. 15, pp. 3346–3354, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  28. A. K. Dunker, Z. Obradović, P. Romero, E. C. Garner, and C. J. Brown, “Intrinsic protein disorder in complete genomes,” Genome Informatics, vol. 11, pp. 161–171, 2000. View at Scopus
  29. J. J. Ward, J. S. Sodhi, L. J. McGuffin, B. F. Buxton, and D. T. Jones, “Prediction and functional analysis of native disorder in proteins from the three kingdoms of life,” Journal of Molecular Biology, vol. 337, no. 3, pp. 635–645, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  30. C. J. Oldfield, Y. Cheng, M. S. Cortese, C. J. Brown, V. N. Uversky, and A. K. Bunker, “Comparing and combining predictors of mostly disordered proteins,” Biochemistry, vol. 44, no. 6, pp. 1989–2000, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  31. R. W. Kriwacki, L. Hengst, L. Tennant, S. I. Reed, and P. E. Wright, “Structural studies of p21Waf1/Cip1/Sdi1 in the free and Cdk2-bound state: conformational disorder mediates binding diversity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 21, pp. 11504–11509, 1996. View at Scopus
  32. E. R. Lacy, I. Filippov, W. S. Lewis, et al., “p27 binds cyclin-CDK complexes through a sequential mechanism involving binding-induced protein folding,” Nature Structural and Molecular Biology, vol. 11, no. 4, pp. 358–364, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  33. E. R. Lacy, Y. Wang, J. Post, et al., “Molecular basis for the specificity of p27 toward cyclin-dependent kinases that regulate cell division,” Journal of Molecular Biology, vol. 349, no. 4, pp. 764–773, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  34. H. J. Dyson and P. E. Wright, “Coupling of folding and binding for unstructured proteins,” Current Opinion in Structural Biology, vol. 12, no. 1, pp. 54–60, 2002. View at Publisher · View at Google Scholar · View at Scopus
  35. C. J. Oldfield, Y. Cheng, M. S. Cortese, P. Romero, V. N. Uversky, and A. K. Dunker, “Coupled folding and binding with alpha-helix-forming molecular recognition elements,” Biochemistry. In press.
  36. Y. Cheng, C. J. Oldfield, J. Meng, P. Romero, V. N. Uversky, and A. K. Dunker, “Mining α-helix-forming molecular recognition features with cross species sequence alignments,” Biochemistry, vol. 46, no. 47, pp. 13468–13477, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  37. A. Mohan, MoRFs: A Dataset of Molecular Recognition Features, The School of Informatics, Indiana University, Indianapolis, Ind, USA, 2006.
  38. V. Vacic, C. J. Oldfield, A. Mohan, et al., “Characterization of molecular recognition features, MoRFs, and their binding partners,” Journal of Proteome Research, vol. 6, no. 6, pp. 2351–2366, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  39. V. N. Uversky, C. J. Oldfield, and A. K. Dunker, “Intrinsically disordered proteins in human diseases: introducing the D2 concept,” Annual Review of Biophysics, vol. 37, pp. 215–246, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  40. M. S. Cortese, J. P. Baird, V. N. Uversky, and A. K. Dunker, “Uncovering the unfoldome: enriching cell extracts for unstructured proteins by acid treatment,” Journal of Proteome Research, vol. 4, no. 5, pp. 1610–1618, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  41. U. Midic, C. J. Oldfield, A. K. Keith, Z. Obradović, and V. N. Uversky, “Protein disorder in the human diseasome: unfoldomics of human genetic diseases,” BMC Genomics, vol. 10, supplement 1, article S12, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  42. H. Winkler, V.u.U.d.P.i.P.-u.T.J.V.F., 1920.
  43. J. Lederberg and A. T. McCray, “‘Ome’ sweet ‘omics’—a genealogical treasury of words,” The Scientist, vol. 15, no. 7, article 8, 2001.
  44. V. N. Uversky, C. J. Oldfield, U. Midic, et al., “Unfoldomics of human diseases: linking protein intrinsic disorder with diseases,” BMC Genomics, vol. 10, supplement 1, article S7, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  45. V. N. Uversky, J. R. Gillespie, and A. L. Fink, “Why are “natively unfolded” proteins unstructured under physiologic conditions?” Proteins, vol. 41, no. 3, pp. 415–427, 2000. View at Scopus
  46. F. Ferron, S. Longhi, B. Canard, and D. Karlin, “A practical overview of protein disorder prediction methods,” Proteins, vol. 65, no. 1, pp. 1–14, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  47. Z. Dosztanyi, M. Sandor, P. Tompa, and I. Simon, “Prediction of protein disorder at the domain level,” Current Protein and Peptide Science, vol. 8, no. 2, pp. 161–171, 2007. View at Publisher · View at Google Scholar · View at Scopus
  48. Z. Dosztanyi and P. Tompa, “Prediction of protein disorder,” Methods in Molecular Biology, vol. 426, pp. 103–115, 2008. View at Scopus
  49. S. J. Hubbard, R. J. Beynon, and J. M. Thornton, “Assessment of conformational parameters as predictors of limited proteolytic sites in native protein structures,” Protein Engineering, vol. 11, no. 5, pp. 349–359, 1998. View at Scopus
  50. L. M. Iakoucheva, A. L. Kimzey, C. D. Masselon, R. D. Smith, A. K. Dunker, and E. J. Ackerman, “Aberrant mobility phenomena of the DNA repair protein XPA,” Protein Science, vol. 10, no. 7, pp. 1353–1362, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  51. R. Reeves and M. S. Nissen, “Purification and assays for high mobility group HMG-I(Y) protein function,” Methods in Enzymology, vol. 304, pp. 155–188, 1999. View at Publisher · View at Google Scholar · View at Scopus
  52. G. W. Daughdrill, G. J. Pielak, V. N. Uversky, M. S. Cortese, and A. K. Dunker, “Natively disordered proteins,” in Handbook of Protein Folding, J. Buchner and T. Kiefhaber , Eds., pp. 271–353, Wiley-VCH, Weinheim, Germany, 2005.
  53. V. Receveur-Bréchot, J.-M. Bourhis, V. N. Uversky, B. Canard, and S. Longhi, “Assessing protein disorder and induced folding,” Proteins, vol. 62, no. 1, pp. 24–45, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  54. V. N. Uversky, “What does it mean to be natively unfolded?” European Journal of Biochemistry, vol. 269, no. 1, pp. 2–12, 2002. View at Publisher · View at Google Scholar · View at Scopus
  55. V. N. Uversky, “Intrinsically disordered proteins and their environment: effects of strong denaturants, temperature, ph, counter ions, membranes, binding partners, osmolytes, and macromolecular crowding,” Protein Journal, vol. 28, no. 7-8, pp. 305–325, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  56. V. Csizmók, E. Szollosi, P. Friedrich, and P. Tompa, “A novel two-dimensional electrophoresis technique for the identification of intrinsically unstructured proteins,” Molecular and Cellular Proteomics, vol. 5, no. 2, pp. 265–273, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  57. C. A. Galea, V. R. Pagala, J. C. Obenauer, C.-G. Park, C. A. Slaughter, and R. W. Kriwacki, “Proteomic studies of the intrinsically unstructured mammalian proteome,” Journal of Proteome Research, vol. 5, no. 10, pp. 2839–2848, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  58. P. Romero, Z. Obradović, C. Kissinger, J. E. Villafranca, and A. K. Dunker, “Identifying disordered regions in proteins from amino acid sequence,” in Proceedings of the IEEE International Conference on Neural Networks, vol. 1, pp. 90–95, 1997. View at Scopus
  59. P. Romero, Z. Obradović, and K. Dunker, “Sequence data analysis for long disordered regions prediction in the calcineurin family,” Genome Informatics, vol. 8, pp. 110–124, 1997.
  60. Q. Xie, G. E. Arnold, P. Romero, Z. Obradović, E. Garner, and A. K. Dunker, “The sequence attribute method for determining relationships between sequence and protein disorder,” Genome Informatics, vol. 9, pp. 193–200, 1998.
  61. P. Romero, Z. Obradović, C. R. Kissinger, et al., “Thousands of proteins likely to have long disordered regions,” Pacific Symposium on Biocomputing, pp. 437–448, 1998. View at Scopus
  62. K. Gast, H. Damaschun, K. Eckert, et al., “Prothymosin α: a biologically active protein with random coil conformation,” Biochemistry, vol. 34, no. 40, pp. 13211–13218, 1995. View at Publisher · View at Google Scholar · View at Scopus
  63. P. H. Weinreb, W. Zhen, A. W. Poon, K. A. Conway, and P. T. Lansbury Jr., “NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded,” Biochemistry, vol. 35, no. 43, pp. 13709–13715, 1996. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  64. H. C. Hemmings Jr., A. C. Nairn, D. W. Aswad, and P. Greengard, “DARPP-32, a dopamine- and adenosine 3:5-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. II. Purification and characterization of the phosphoprotein from bovine caudate nucleus,” Journal of Neuroscience, vol. 4, no. 1, pp. 99–110, 1984. View at Scopus
  65. R. J. Williams, “The conformational mobility of proteins and its functional significance,” Biochemical Society Transactions, vol. 6, no. 6, pp. 1123–1126, 1978. View at Scopus
  66. A. K. Dunker, E. Garner, S. Guilliot, et al., “Protein disorder and the evolution of molecular recognition: theory, predictions and observations,” Pacific Symposium on Biocomputing, pp. 473–484, 1998. View at Scopus
  67. E. Garner, P. Cannon, P. Romero, Z. Obradović, and A. K. Dunker, “Predicting disordered regions from amino acid sequence: common themes despite differing structural characterization,” Genome Informatics, vol. 9, pp. 201–213, 1998.
  68. M. Vihinen, E. Torkkila, and P. Riikonen, “Accuracy of protein flexibility predictions,” Proteins, vol. 19, no. 2, pp. 141–149, 1994. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  69. R. M. Williams, Z. Obradović, V. Mathura, et al., “The protein non-folding problem: amino acid determinants of intrinsic order and disorder,” Pacific Symposium on Biocomputing, pp. 89–100, 2001. View at Scopus
  70. P. Romero, Z. Obradović, X. Li, E. C. Garner, C. J. Brown, and A. K. Dunker, “Sequence complexity of disordered protein,” Proteins, vol. 42, no. 1, pp. 38–48, 2001. View at Publisher · View at Google Scholar · View at Scopus
  71. X. Li, Z. Obradović, C. J. Brown, E. C. Garner, and A. K. Dunker, “Comparing predictors of disordered protein,” Genome Informatics, vol. 11, pp. 172–184, 2000. View at Scopus
  72. P. Radivojac, Z. Obradović, D. K. Smith, et al., “Protein flexibility and intrinsic disorder,” Protein Science, vol. 13, no. 1, pp. 71–80, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  73. S. Vucetic, C. J. Brown, A. K. Dunker, and Z. Obradović, “Flavors of protein disorder,” Proteins, vol. 52, no. 4, pp. 573–584, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  74. X. Li, P. Romero, M. Rani, A. K. Dunker, and Z. Obradović, “Predicting protein disorder for N-, C-, and internal regions,” Genome Informatics, vol. 10, pp. 30–40, 1999.
  75. K. Peng, S. Vucetic, P. Radivojac, C. J. Brown, A. K. Dunker, and Z. Obradović, “Optimizing long intrinsic disorder predictors with protein evolutionary information,” Journal of Bioinformatics and Computational Biology, vol. 3, no. 1, pp. 35–60, 2005. View at Publisher · View at Google Scholar · View at Scopus
  76. Z. Obradović, K. Peng, S. Vucetic, P. Radivojac, and A. K. Bunker, “Exploiting heterogeneous sequence properties improves prediction of protein disorder,” Proteins, vol. 61, supplement 7, pp. 176–182, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  77. K. Peng, P. Radivojac, S. Vucetic, A. K. Dunker, and Z. Obradović, “Length-dependent prediction of protein in intrinsic disorder,” BMC Bioinformatics, vol. 7, article 208, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  78. J. Prilusky, C. E. Felder, T. Zeev-Ben-Mordehai, et al., “FoldIndex©: a simple tool to predict whether a given protein sequence is intrinsically unfolded,” Bioinformatics, vol. 21, no. 16, pp. 3435–3438, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  79. R. Linding, R. B. Russell, V. Neduva, and T. J. Gibson, “GlobPlot: exploring protein sequences for globularity and disorder,” Nucleic Acids Research, vol. 31, no. 13, pp. 3701–3708, 2003. View at Publisher · View at Google Scholar · View at Scopus
  80. R. Linding, L. J. Jensen, F. Diella, P. Bork, T. J. Gibson, and R. B. Russell, “Protein disorder prediction: implications for structural proteomics,” Structure, vol. 11, no. 11, pp. 1453–1459, 2003. View at Publisher · View at Google Scholar · View at Scopus
  81. D. T. Jones and J. J. Ward, “Prediction of disordered regions in proteins from position specific score matrices,” Proteins, vol. 53, supplement 6, pp. 573–578, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  82. J. J. Ward, L. J. McGuffin, K. Bryson, B. F. Buxton, and D. T. Jones, “The DISOPRED server for the prediction of protein disorder,” Bioinformatics, vol. 20, no. 13, pp. 2138–2139, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  83. K. Bryson, L. J. McGuffin, R. L. Marsden, J. J. Ward, J. S. Sodhi, and D. T. Jones, “Protein structure prediction servers at University College London,” Nucleic Acids Research, vol. 33, supplement 2, pp. W36–W38, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  84. Z. Dosztanyi, V. Csizmok, P. Tompa, and I. Simon, “IUPred: web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content,” Bioinformatics, vol. 21, no. 16, pp. 3433–3434, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  85. O. V. Galzitskaya, S. O. Garbuzynskiy, and M. Y. Lobanov, “FoldUnfold: web server for the prediction of disordered regions in protein chain,” Bioinformatics, vol. 22, no. 23, pp. 2948–2949, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  86. Z. R. Yang, R. Thomson, P. McNeil, and R. M. Esnouf, “RONN: the bio-basis function neural network technique applied to the detection of natively disordered regions in proteins,” Bioinformatics, vol. 21, no. 16, pp. 3369–3376, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  87. C.-T. Su, C.-Y. Chen, and Y.-Y. Ou, “Protein disorder prediction by condensed PSSM considering propensity for order or disorder,” BMC Bioinformatics, vol. 7, article 319, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  88. C. T. Su, C. Y. Chen, and C. M. Hsu, “iPDA: integrated protein disorder analyzer,” Nucleic Acids Research, vol. 35, web server issue, pp. W465–W472, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  89. A. Vullo, O. Bortolamil, G. Pollastri, and S. C. E. Tosatto, “Spritz: a server for the prediction of intrinsically disordered regions in protein sequences using kernel machines,” Nucleic Acids Research, vol. 34, web server issue, pp. W164–W168, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  90. T. Ishida and K. Kinoshita, “PrDOS: prediction of disordered protein regions from amino acid sequence,” Nucleic Acids Research, vol. 35, web server issue, pp. W460–W464, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  91. B. He, K. Wang, Y. Liu, B. Xue, V. N. Uversky, and A. K. Dunker, “Predicting intrinsic disorder in proteins: an overview,” Cell Research, vol. 19, no. 8, pp. 929–949, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  92. A. Mohan, W. J. Sullivan Jr., P. Radivojac, A. K. Dunker, and V. N. Uversky, “Intrinsic disorder in pathogenic and non-pathogenic microbes: discovering and analyzing the unfoldomes of early-branching eukaryotes,” Molecular BioSystems, vol. 4, no. 4, pp. 328–340, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  93. K. I. Rantalainen, V. N. Uversky, P. Permi, N. Kalkkinen, A. K. Dunker, and K. Mäkinen, “Potato virus A genome-linked protein VPg is an intrinsically disordered molten globule-like protein with a hydrophobic core,” Virology, vol. 377, no. 2, pp. 280–288, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  94. E. Hébrard, Y. Bessin, T. Michon, et al., “Intrinsic disorder in Viral Proteins Genome-Linked: experimental and predictive analyses,” Virology Journal, vol. 6, article 23, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  95. V. N. Uversky, A. Roman, C. J. Oldfield, and A. K. Dunker, “Protein intrinsic disorder and human papillomaviruses: increased amount of disorder in E6 and E7 oncoproteins from high risk HPVs,” Journal of Proteome Research, vol. 5, no. 8, pp. 1829–1842, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  96. Y. Cheng, T. LeGall, C. J. Oldfield, A. K. Dunker, and V. N. Uversky, “Abundance of intrinsic disorder in protein associated with cardiovascular disease,” Biochemistry, vol. 45, no. 35, pp. 10448–10460, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  97. V. N. Uversky, “Intrinsic disorder in proteins associated with neurodegenerative diseases,” Frontiers in Bioscience, vol. 14, pp. 5188–5238, 2009. View at Scopus
  98. K.-I. Goh, M. E. Cusick, D. Valle, B. Childs, M. Vidal, and A.-L. Barabási, “The human disease network,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 21, pp. 8685–8690, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  99. V. N. Uversky, “A protein-chameleon: conformational plasticity of α-synuclein, a disordered protein involved in neurodegenerative disorders,” Journal of Biomolecular Structure and Dynamics, vol. 21, no. 2, pp. 211–234, 2003. View at Scopus
  100. V. N. Uversky, J. R. Gillespie, I. S. Millett, et al., “Natively unfolded human prothymosin α adopts partially folded collapsed conformation at acidic pH,” Biochemistry, vol. 38, no. 45, pp. 15009–15016, 1999. View at Publisher · View at Google Scholar · View at Scopus
  101. Y. Goto, L. J. Calciano, and A. L. Fink, “Acid-induced folding of proteins,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 2, pp. 573–577, 1990. View at Scopus
  102. Y. Goto and A. L. Fink, “Phase diagram for acidic conformational states of apomyoglobin,” Journal of Molecular Biology, vol. 214, no. 4, pp. 803–805, 1990. View at Publisher · View at Google Scholar · View at Scopus
  103. Y. Goto, N. Takahashi, and A. L. Fink, “Mechanism of acid-induced folding of proteins,” Biochemistry, vol. 29, no. 14, pp. 3480–3488, 1990. View at Scopus
  104. A. L. Fink, L. J. Calciano, Y. Goto, T. Kurotsu, and D. R. Palleros, “Classification of acid denaturation of proteins: intermediates and unfolded states,” Biochemistry, vol. 33, no. 41, pp. 12504–12511, 1994. View at Scopus
  105. E. A. Bienkiewicz, J. N. Adkins, and K. J. Lumb, “Functional consequences of preorganized helical structure in the intrinsically disordered cell-cycle inhibitor p27Kip1,” Biochemistry, vol. 41, no. 3, pp. 752–759, 2002. View at Publisher · View at Google Scholar · View at Scopus
  106. L. Hengst, V. Dulic, J. M. Slingerland, E. Lees, and S. I. Reed, “A cell cycle-regulated inhibitor of cyclin-dependent kinases,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 12, pp. 5291–5295, 1994. View at Publisher · View at Google Scholar · View at Scopus
  107. V. N. Uversky, J. Li, and A. L. Fink, “Evidence for a partially folded intermediate in α-synuclein fibril formation,” Journal of Biological Chemistry, vol. 276, no. 14, pp. 10737–10744, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  108. J. Li, V. N. Uversky, and A. L. Fink, “Effect of familial Parkinson's disease point mutations A30P and A53T on the structural properties, aggregation, and fibrillation of human α-synuclein,” Biochemistry, vol. 40, no. 38, pp. 11604–11613, 2001. View at Publisher · View at Google Scholar · View at Scopus
  109. V. N. Uversky, S. E. Permyakov, V. E. Zagranichny, et al., “Effect of zinc and temperature on the conformation of the γ subunit of retinal phosphodiesterase: a natively unfolded protein,” Journal of Proteome Research, vol. 1, no. 2, pp. 149–159, 2002. View at Publisher · View at Google Scholar · View at Scopus
  110. V. N. Uversky, J. Li, P. Souillac, et al., “Biophysical properties of the synucleins and their propensities to fibrillate: inhibition of α-synuclein assembly by β- and γ-synucleins,” Journal of Biological Chemistry, vol. 277, no. 14, pp. 11970–11978, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  111. S. E. Permyakov, I. S. Millett, S. Doniach, E. A. Permyakov, and V. N. Uversky, “Natively unfolded C-terminal domain of caldesmon remains substantially unstructured after the effective binding to calmodulin,” Proteins, vol. 53, no. 4, pp. 855–862, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  112. M. Häckel, T. Konno, and H.-J. Hinz, “A new alternative method to quantify residual structure in ‘unfolded’ proteins,” Biochimica et Biophysica Acta, vol. 1479, no. 1-2, pp. 155–165, 2000. View at Publisher · View at Google Scholar · View at Scopus
  113. L. D. Belmont and T. J. Mitchison, “Identification of a protein that interacts with tubulin dimers and increases the catastrophe rate of microtubules,” Cell, vol. 84, no. 4, pp. 623–631, 1996. View at Publisher · View at Google Scholar · View at Scopus
  114. M. A. Hernandez, J. Avila, and J. M. Andreu, “Physicochemical characterization of the heat-stable microtubule-associated protein MAP2,” European Journal of Biochemistry, vol. 154, no. 1, pp. 41–48, 1986. View at Scopus
  115. C. Kalthoff, “A novel strategy for the purification of recombinantly expressed unstructured protein domains,” Journal of Chromatography B, vol. 786, no. 1-2, pp. 247–254, 2003. View at Publisher · View at Google Scholar · View at Scopus