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Natively Disordered Proteins

Functions and Predictions

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Proteins can exist in at least three forms: the ordered form (solid-like), the partially folded form (collapsed, molten globule-like or liquid-like) and the extended form (extended, random coil-like or gas-like). The protein trinity hypothesis has two components: (i) a given native protein can be in any one of the three forms, depending on the sequence and the environment; and (ii) function can arise from any one of the three forms or from transitions between them. In this study, bioinformatics and data mining were used to investigate intrinsic disorder in proteins and develop neural network-based predictors of natural disordered regions (PONDR) that can discriminate between ordered and disordered residues with up to 84% accuracy. Predictions of intrinsic disorder indicate that the three kingdoms follow the disorder ranking eubacteria < archaebacteria ≪ eukaryotes, with approximately half of eukaryotic proteins predicted to contain substantial regions of intrinsic disorder. Many of the known disordered regions are involved in signalling, regulation or control. Involvement of highly flexible or disordered regions in signalling is logical: a flexible sensor more readily undergoes conformational change in response to environmental perturbations than does a rigid one. Thus, the increased disorder in the eukaryotes is likely the direct result of an increased need for signalling and regulation in nucleated organisms. PONDR can also be used to detect molecular recognition elements that are disordered in the unbound state and become structured when bound to a biologically meaningful partner. Application of disorder predictions to cell-signalling, cancer-associated and control protein databases supports the widespread occurrence of protein disorder in these processes.

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  1. 1.

    Fischer E. Einfluss der configuration auf die Wirkung der enzyme. Berichte Deutsche Chemische Gesellschaft 1894; 27: 2985–93

  2. 2.

    Wu H. Studies on denaturation of proteins XIII: a theory of denaturation. Chin J Physiol 1931; 1: 219–34

  3. 3.

    Mirsky AE, Pauling L. On the structure of native, denatured and coagulated proteins. Proc Natl Acad Sci U S A 1936; 22: 439–47

  4. 4.

    Berman HM, Westbrook J, Feng Z, et al. The Protein Data Bank. Nucleic Acids Res 2000; 28: 235–42

  5. 5.

    Uversky VN, Gillespie JR, Millett IS, et al. Natively unfolded human prothymosin alpha adopts partially folded collapsed conformation at acidic pH. Biochemistry 1999; 38: 15009–16

  6. 6.

    Wright PE, Dyson HJ. Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm. J Mol Biol 1999; 293: 321–31

  7. 7.

    Weinreb PH, Zhen W, Poon AW, et al. NACP, a protein implicated in Alzheimer’s disease and learning, is natively unfolded. Biochemistry 1996; 35: 13709–15

  8. 8.

    Dunker AK, Brown CJ, Lawson JD, et al. Intrinsic disorder and protein function. Biochemistry 2002; 41: 6573–82

  9. 9.

    Tompa P. Intrinsically unstructured proteins. Trends Biochem Sci 2002; 27: 527–33

  10. 10.

    Namba K. Roles of partly unfolded conformations in macromolecular self-assembly. Genes Cells 2001; 6: 1–12

  11. 11.

    Meador WE, Means AR, Quiocho FA. Target enzyme recognition by calmodulin: 2.4 A structure of a camodulin-peptide complex. Science 1992; 257: 1251–5

  12. 12.

    Dunker AK, Lawson JD, Brown CJ, et al. Intrinsically disordered protein. J Mol Graph Model 2001; 19: 26–59

  13. 13.

    Bailey RW, Dunker AK, Brown CJ, et al. Clusterin: a binding protein with a molten globule-like region. Biochemistry 2001; 40: 11828–40

  14. 14.

    Romero P, Obradovic Z, Dunker AK. Intelligent data analysis for protein disorder prediction. Artif Intell Rev 2000; 14: 447–84

  15. 15.

    Romero P, Obradovic Z, Kissinger CR, et al. Identifying disordered regions in proteins from amino acid sequences. IEEE International Joint Conference on Neural Networks; 1997 Jun 9–12; Houston (TX), 90–5

  16. 16.

    Vucetic S, Radivojac P, Obradovic Z, et al. Methods for improving protein disorder prediction. IEEE International Joint Conference on Neural Networks; 2001 Jul 15–19; Washington, DC, 2718–23

  17. 17.

    Iakoucheva LM, Kimzey AL, Masselon CD, et al. Identification of intrinsic order and disorder in the DNA repair protein XPA. Protein Sci 2001; 10: 560–71

  18. 18.

    Dunker AK, Obradovic Z, Romero P, et al. Intrinsic protein disorder in complete genomes. Genome Inform Ser Workshop Genome Inform 2000; 11: 161–71

  19. 19.

    Schulz GE. Nucleotide binding proteins. In: Balaban M, editor. Molecular mechanism of biological recognition. New York: Elsevier/North-Holland Biomedical Press, 1979: 79–94

  20. 20.

    Kriwacki RW, Hengst L, Tennant L, et al. Structural studies of p21Waf1/Cip1/Sdi1 in the free and Cdk2-bound state: conformational disorder mediates binding diversity. Proc Natl Acad Sci U S A 1996; 93: 11504–9

  21. 21.

    Jeong H, Mason SP, Barabasi AL, et al. Lethality and centrality in protein networks. Nature 2001; 411: 41–2

  22. 22.

    Reeves R. Molecular biology of HMGA proteins: hubs of nuclear function. Gene 2001; 277: 63–81

  23. 23.

    Huth JR, Bewley CA, Nissen MS, et al. The solution structure of an HMG-I(Y)-DNA complex defines a new architectural minor groove binding motif. Nat Struct Biol 1997; 4: 657–65

  24. 24.

    Fletcher CM, McGuire AM, Gingras AC, et al. 4E binding proteins inhibit the translation factor eIF4E without folded structure. Biochemistry 1998; 37: 9–15

  25. 25.

    Fletcher CM, Wagner G. The interaction of eIF4E with 4E-BP1 is an induced fit to a completely disordered protein. Protein Sci 1998; 7: 1639–42

  26. 26.

    Mader S, Lee H, Pause A, et al. The translation initiation factor eIF-4E binds to a common motif shared by the translation factor eIF-4 gamma and the translational repressors 4E-binding proteins. Mol Cell Biol 1995; 15: 4990–7

  27. 27.

    Marcotrigiano J, Gingras AC, Sonenberg N, et al. Cap-dependent translation initiation in eukaryotes is regulated by a molecular mimic of eIF4G. Mol Cell 1999; 3: 707–16

  28. 28.

    Kussie PH, Gorina S, Marechal V, et al. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 1996; 274: 948–53

  29. 29.

    Lee H, Mok KH, Muhandiram R, et al. Local structural elements in the mostly unstructured transcriptional activation domain of human p53. J Biol Chem 2000; 275: 29426–32

  30. 30.

    Rustandi RR, Baldisseri DM, Weber DJ. Structure of the negative regulatory domain of p53 bound to S100B(betabeta). Nat Struct Biol 2000; 7: 570–4

  31. 31.

    Bourhis JM, Johansson K, Receveur-Brechot V, et al. The C-terminal domain of measles virus nucleoprotein belongs to the class of intrinsically disordered proteins that fold upon binding to their physiological partner. Virus Res 2004; 99: 157–67

  32. 32.

    Vucetic S, Brown CJ, Dunker AK, et al. Flavors of protein disorder. Proteins 2003; 52: 573–84

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This work has been supported by the Indiana Genomics Initiative (INGEN), which in turn is funded in part by the Lilly Endowment. NIH grant 1-RO1-LM007688-01A1 also provided support.

There are no potential conflicts of interest directly relevant to the content of this study.

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Correspondence to Dr Pedro Romero.

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Romero, P., Obradovic, Z. & Dunker, A.K. Natively Disordered Proteins. Appl-Bioinformatics 3, 105–113 (2004). https://doi.org/10.2165/00822942-200403020-00005

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  • Nuclear Magnetic Resonance
  • Intrinsic Disorder
  • Sequence Window
  • Label Dataset
  • Disorder Prediction