Skip to main content

Fuzzy Complexes: A More Stochastic View of Protein Function

  • Chapter
Book cover Fuzziness

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 725))

Abstract

Intrinsically disordered proteins (IDPs) are widespread in eukaryotic proteomes and challenge the classical structure-function paradigm that equates a folded 3-D structure with protein function. However, IDPs often function by molecular recognition, in which they bind a partner molecule and undergo “induced folding” or “disorder-to-order transition” upon binding, which apparently suggests that in a functional context IDPs become ordered. Whereas this observation would restore the “prestige” of the classical structure-function paradigm, a closer inspection of the complexes of IDPs reveals that they do not always become fully ordered, but preserve functionally significant disorder in the complex with their binding partner(s). This phenomenon, which we termed “fuzziness”, is the ultimate extension of structural disorder to the functional native state of proteins. In this introductory chapter, we outline the most important aspects of fuzziness, such as its structural categories, molecular mechanisms of function it mediates and the biological processes, in which it plays a distinguished role. As confirmed by all the other chapters of the book, we will show that new cases of fuzziness pop up at an accelerating pace, underscoring that this phenomenon presents a widespread novel paradigm of protein structure and function.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Warshel A, Sharma PK, Kato M et al. Electrostatic basis for enzyme catalysis. Chem Rev 2006; 106: 3210–3235.

    Article  PubMed  CAS  Google Scholar 

  2. H enzler-Wildman KA, Thai V, Lei M et al. Intrinsic motions along an enzymatic reaction trajectory. Nature 2007; 450:838–44.

    Article  PubMed  CAS  Google Scholar 

  3. Todd AE, Orengo CA, Thornton JM. Plasticity of enzyme active sites. Trends Biochem Sci 2002; 27: 419–26.

    Article  PubMed  CAS  Google Scholar 

  4. Freedman SJ, Sun ZY, Kung AL et al. Structural basis for negative regulation of hypoxia-inducible factor-1alpha by CITED2. Nat Struct Biol 2003; 10:504–12.

    Article  PubMed  CAS  Google Scholar 

  5. del Sol A, Tsai CJ, Ma B et al. The origin of allosteric functional modulation: multiple pre-existing pathways. Structure 2009; 17:1042–50.

    Article  PubMed  Google Scholar 

  6. Romero P, Obradovic Z, Kissinger CR et al. Thousands of proteins likely to have long disordered regions. Pac Symp Biocomputing 1998; 3:437–48.

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  9. Sickmeier M, Hamilton JA, LeGall T et al. DisProt: the Database of Disordered Proteins. Nucleic Acids Res 2007; 35:D786–D793.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  11. Tompa P, Dosztanyi Z, Simon I. Prevalent structural disorder in E. coli and S. cerevisiae proteomes. J Proteome Res 2006; 5:1996–2000.

    Article  PubMed  CAS  Google Scholar 

  12. Ward JJ, Sodhi JS, McGuffin LJ et al. Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J Mol Biol 2004; 337:635–45.

    Article  PubMed  CAS  Google Scholar 

  13. Xie H, Vucetic S, Iakoucheva LM et al. Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions. J Proteome Res 2007; 6:1882–98.

    Article  PubMed  CAS  Google Scholar 

  14. Fuxreiter M, Tompa P, Simon I et al. Malleable machines take shape in eukaryotic transcriptional regulation. Nat Chem Biol 2008; 4:728–37.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  16. Uversky VN, Oldfield CJ, Dunker AK. Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling. J Mol Recognit 2005; 18:343–84.

    Article  PubMed  CAS  Google Scholar 

  17. Tompa P. The interplay between structure and function in intrinsically unstructured proteins. FEBS Lett 2005; 579:3346–54.

    Article  PubMed  CAS  Google Scholar 

  18. James LC, Roversi P, Tawfik DS. Antibody multispecificity mediated by conformational diversity. Science 2003; 299:1362–67.

    Article  PubMed  CAS  Google Scholar 

  19. Wright PE, Dyson HJ. Linking folding and binding. Curr Opin Struct Biol 2009; 19:31–38.

    Article  PubMed  CAS  Google Scholar 

  20. Fuxreiter M, Simon I, Friedrich P et al. Preformed structural elements feature in partner recognition by intrinsically unstructured proteins. J Mol Biol 2004; 338:1015–26.

    Article  PubMed  CAS  Google Scholar 

  21. Patel SS, Belmont BJ, Sante JM et al. Natively unfolded nucleoporins gate protein diffusion across the nuclear pore complex. Cell 2007; 129:83–96.

    Article  PubMed  CAS  Google Scholar 

  22. Tompa P, Fuxreiter M. Fuzzy complexes: polymorphism and structural disorder in protein-protein interactions. Trends Biochem Sci 2008; 33:2–8.

    Article  PubMed  CAS  Google Scholar 

  23. Fontes MR, Teh T, Toth G et al. Role of flanking sequences and phosphorylation in the recognition of the simian-virus-40 large T-antigen nuclear localization sequences by importin-alpha. Biochem J 2003; 375:339–49.

    Article  PubMed  CAS  Google Scholar 

  24. Graham TA, Ferkey DM, Mao F et al. Tcf4 can specifically recognize beta-catenin using alternative conformations. Nat Struct Biol 2001; 8:1048–52.

    Article  PubMed  CAS  Google Scholar 

  25. Renault L, Bugyi B, Carlier MF. Spire and Cordon-bleu: multifunctional regulators of actin dynamics. Trends Cell Biol 2008; 18:494–504.

    Article  PubMed  CAS  Google Scholar 

  26. Haarmann CS, Green D, Casarotto MG et al. The random-coil ‘C’ fragment of the dihydropyridine receptor II-III loop can activate or inhibit native skeletal ryanodine receptors. Biochem J 2003; 372:305–16.

    Article  PubMed  CAS  Google Scholar 

  27. Bhattacharyya RP, Remenyi A, Good MC et al. The Ste5 scaffold allosterically modulates signaling output of the yeast mating pathway. Science 2006; 311:822–26.

    Article  PubMed  CAS  Google Scholar 

  28. van Leeuwen HC, Strating MJ, Rensen M et al. Linker length and composition influence the flexibility of Oct-1 DNA binding. C. EMBO J 1997; 16:2043–53.

    Article  Google Scholar 

  29. Rock RS, Ramamurthy B, Dunn AR et al. A flexible domain is essential for the large step size and processivity of myosin VI. Mol Cell 2005; 17:603–09.

    Article  PubMed  CAS  Google Scholar 

  30. Neduva V, Russell RB. Linear motifs: evolutionary interaction switches. FEBS Lett 2005; 579:3342–45.

    Article  PubMed  CAS  Google Scholar 

  31. Fuxreiter M, Tompa P, Simon I. Local structural disorder imparts plasticity on linear motifs. Bioinformatics 2007; 23:950–56.

    Article  PubMed  CAS  Google Scholar 

  32. Zor T, Mayr BM, Dyson HJ et al. Roles of phosphorylation and helix propensity in the binding of the KIX domain of CREB-binding protein by constitutive (c-Myb) and inducible (CREB) activators. J Biol Chem 2002; 277:42241–48.

    Article  PubMed  CAS  Google Scholar 

  33. Selenko P, Gregorovic G, Sprangers R et al. Structural basis for the molecular recognition between human splicing factors U2AF65 and SF1/mBBP. Mol Cell 2003; 11:965–76.

    Article  PubMed  CAS  Google Scholar 

  34. Liu Y, Matthews KS, Bondos SE. Multiple intrinsically disordered sequences alter DNA binding by the homeodomain of the Drosophila hox protein ultrabithorax. J Biol Chem 2008; 283:20874–87.

    Article  PubMed  CAS  Google Scholar 

  35. Phylip LH, Lees WE, Brownsey BG et al. The potency and specificity of the interaction between the IA3 inhibitor and its target aspartic proteinase from Saccharomyces cerevisiae. J Biol Chem 2001; 276:2023–30.

    Article  PubMed  CAS  Google Scholar 

  36. Yu H, Chen JK, Feng S et al. Structural basis for the binding of proline-rich peptides to SH3 domains. Cell 1994; 76:933–45.

    Article  PubMed  CAS  Google Scholar 

  37. Billeter M, Qian YQ, Otting G et al. Determination of the nuclear magnetic resonance solution structure of an Antennapedia homeodomain-DNA complex. J Mol Biol 1993; 234:1084–93.

    Article  PubMed  CAS  Google Scholar 

  38. Simon SM, Sousa FJ, Mohana-Borges R et al. Regulation of Escherichia coli SOS mutagenesis by dimeric intrinsically disordered umuD gene products. Proc Natl Acad Sci USA 2008; 105:1152–57.

    Article  PubMed  CAS  Google Scholar 

  39. Sigalov A, Aivazian D, Stern L. Homooligomerization of the cytoplasmic domain of the T cell receptor zeta chain and of other proteins containing the immunoreceptor tyrosine-based activation motif. Biochemistry 2004; 43:2049–61.

    Article  PubMed  CAS  Google Scholar 

  40. Savvides SN, Raghunathan S, Futterer K et al. The C-terminal domain of full-length E. coli SSB is disordered even when bound to DNA. Protein Sci 2004; 13:1942–47.

    Article  PubMed  CAS  Google Scholar 

  41. Hope IA, Mahadevan S, Struhl K. Structural and functional characterization of the short acidic transcriptional activation region of yeast GCN4 protein. Nature 1988; 333:635–40.

    Article  PubMed  CAS  Google Scholar 

  42. Sigler PB. Transcriptional activation. Acid blobs and negative noodles. Nature 1988; 333:210–12.

    Article  PubMed  CAS  Google Scholar 

  43. Ng KP, Potikyan G, Savene RO et al. Multiple aromatic side chains within a disordered structure are critical for transcription and transforming activity of EWS family oncoproteins. Proc Natl Acad Sci USA 2007; 104:479–84.

    Article  PubMed  CAS  Google Scholar 

  44. Hansen JC, Lu X, Ross ED et al. Intrinsic protein disorder, amino acid composition, and histone terminal domains. J Biol Chem 2006; 281:1853–56.

    Article  PubMed  CAS  Google Scholar 

  45. Lu X, Hamkalo B, Parseghian MH et al. Chromatin condensing functions of the linker histone C-terminal domain are mediated by specific amino acid composition and intrinsic protein disorder. Biochemistry 2009; 48:164–72.

    Article  PubMed  CAS  Google Scholar 

  46. McBryant SJ, Klonoski J, Sorensen TC et al. Determinants of histone H4 N-terminal domain function during nucleosomal array oligomerization: roles of amino acid sequence, domain length, and charge density. J Biol Chem 2009; 284:16716–22.

    Article  PubMed  CAS  Google Scholar 

  47. Krishnan R, Lindquist SL. Structural insights into a yeast prion illuminate nucleation and strain diversity. Nature 2005; 435:765–72.

    Article  PubMed  CAS  Google Scholar 

  48. Ross ED, Edskes HK, Terry MJ et al. Primary sequence independence for prion formation. Proc Natl Acad Sci USA 2005; 102:12825–30.

    Article  PubMed  CAS  Google Scholar 

  49. Mittag T, Orlicky S, Choy WY et al. Dynamic equilibrium engagement of a polyvalent ligand with a single-site receptor. Proc Natl Acad Sci USA 2008; 105:17772–77.

    Article  PubMed  CAS  Google Scholar 

  50. Iakoucheva LM, Radivojac P, Brown CJ et al. The importance of intrinsic disorder for protein phosphorylation. Nucleic Acids Res 2004; 32:1037–49.

    Article  PubMed  CAS  Google Scholar 

  51. Borg M, Mittag T, Pawson T et al. Polyelectrostatic interactions of disordered ligands suggest a physical basis for ultrasensitivity. Proc Natl Acad Sci USA 2007; 104:9650–55.

    Article  PubMed  CAS  Google Scholar 

  52. Baker JM, Hudson RP, Kanelis V et al. CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices. Nat Struct Mol Biol 2007; 14:738–45.

    Article  PubMed  CAS  Google Scholar 

  53. Lacy ER, Filippov I, Lewis WS et al. p27 binds cyclin-CDK complexes through a sequential mechanism involving binding-induced protein folding. Nat Struct Mol Biol 2004; 11:358–64.

    Article  PubMed  CAS  Google Scholar 

  54. Galea CA, Nourse A, Wang Y et al. Role of intrinsic flexibility in signal transduction mediated by the cell cycle regulator, p27 Kip1. J Mol Biol 2008; 376:827–38.

    Article  PubMed  CAS  Google Scholar 

  55. Polverini E, Rangaraj G, Libich DS et al. Binding of the proline-rich segment of myelin basic protein to SH3 domains: spectroscopic, microarray, and modeling studies of ligand conformation and effects of posttranslational modifications. Biochemistry 2008; 47:267–82.

    Article  PubMed  CAS  Google Scholar 

  56. Ahmed MA, Bamm VV, Shi L et al. Induced secondary structure and polymorphism in an intrinsically disordered structural linker of the CNS: solid-state NMR and FTIR spectroscopy of myelin basic protein bound to actin. Biophys J 2009; 96:180–91.

    Article  PubMed  CAS  Google Scholar 

  57. Damante G, Pellizzari L, Esposito G et al. A molecular code dictates sequence-specific DNA recognition by homeodomains. EMBO J 1996; 15:4992–5000.

    PubMed  CAS  Google Scholar 

  58. Toth-Petroczy A, Simon I, Fuxreiter M et al. Disordered tails of homeodomains facilitate DNA recognition by providing a trade-off between folding and specific binding. J Am Chem Soc 2009; 131:15084–85.

    Article  PubMed  CAS  Google Scholar 

  59. Clerici M, Mourao A, Gutsche I et al. Unusual bipartite mode of interaction between the nonsense-mediated decay factors, UPF1 and UPF2. EMBO J 2009; 28:2293–306.

    Article  PubMed  CAS  Google Scholar 

  60. Corden JL. Tails of RNA polymerase II. Trends Biochem Sci 1990; 15:383–87.

    Article  PubMed  CAS  Google Scholar 

  61. Proudfoot NJ, Furger A, Dye MJ. Integrating mRNA processing with transcription. Cell 2002; 108: 501–12.

    Article  PubMed  CAS  Google Scholar 

  62. Ha NC, Tonozuka T, Stamos JL et al. Mechanism of phosphorylation-dependent binding of APC to beta-catenin and its role in beta-catenin degradation. Mol Cell 2004; 15:511–21.

    Article  PubMed  CAS  Google Scholar 

  63. Luger K, Mader AW, Richmond RK et al. J. Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 1997; 389:251–60.

    Article  PubMed  CAS  Google Scholar 

  64. Jenuwein T, Allis CD. Translating the histone code. Science 2001; 293:1074–1080.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  66. Taatjes DJ, Marr MT, Tjian R. Regulatory diversity among metazoan co-activator complexes. Nat Rev Mol Cell Biol 2004; 5:403–10.

    Article  PubMed  CAS  Google Scholar 

  67. Chung WH, Craighead JL, Chang WH et al. RNA polymerase II/TFIIF structure and conserved organization of the initiation complex. Mol Cell 2003; 12:1003–13.

    Article  PubMed  CAS  Google Scholar 

  68. Bubunenko MG, Chuikov SV, Gudkov AT. The length of the interdomain region of the L7/L12 protein is important for its function. FEBS Lett 1992; 313:232–34.

    Article  PubMed  CAS  Google Scholar 

  69. Galea CA, Wang Y, Sivakolundu SG et al. Regulation of cell division by intrinsically unstructured proteins: intrinsic flexibility, modularity, and signaling conduits. Biochemistry 2008; 47:7598–609.

    Article  PubMed  CAS  Google Scholar 

  70. Bernard C, Gely S, Bourhis JM et al. Interaction between the C-terminal domains of N and P proteins of measles virus investigated by NMR. FEBS Lett 2009; 583:1084–89.

    Article  PubMed  CAS  Google Scholar 

  71. Bourhis JM, Canard B, Longhi S. Structural disorder within the replicative complex of measles virus: functional implications. Virology 2006; 344:94–110.

    Article  PubMed  CAS  Google Scholar 

  72. Shi W, Huang Y, Sutton-Smith M et al. A filovirus-unique region of Ebola virus nucleoprotein confers aberrant migration and mediates its incorporation into virions. J Virol 2008; 82:6190–99.

    Article  PubMed  CAS  Google Scholar 

  73. Chiti F, Dobson CM. Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem 2006; 75:333–66.

    Article  PubMed  CAS  Google Scholar 

  74. Chen M, Margittai M, Chen J et al. Investigation of alpha-synuclein fibril structure by site-directed spin labeling. J Biol Chem 2007; 282(34):24970–79.

    Article  PubMed  CAS  Google Scholar 

  75. Margittai M, Langen R. Fibrils with parallel in-register structure constitute a major class of amyloid fibrils: molecular insights from electron paramagnetic resonance spectroscopy. Q Rev Biophys 2008; 41:265–97.

    Article  PubMed  CAS  Google Scholar 

  76. Tompa P. Structural disorder in amyloid fibrils: its implication in dynamic interactions of proteins. FEBS J 2009; 276:5406–15.

    Article  PubMed  CAS  Google Scholar 

  77. Cliff MJ, Harris R, Barford D et al. Conformational diversity in the TPR domain-mediated interaction of protein phosphatase 5 with Hsp90. Structure 2006; 14:415–26.

    Article  PubMed  CAS  Google Scholar 

  78. Hurley TD, Yang J, Zhang L et al. Structural basis for regulation of protein phosphatase 1 by inhibitor-2. J Biol Chem 2007; 282:28874–83.

    Article  PubMed  CAS  Google Scholar 

  79. Kover KE, Bruix M, Santoro J et al. The solution structure and dynamics of human pancreatic ribonuclease determined by NMR spectroscopy provide insight into its remarkable biological activities and inhibition. J Mol Biol 2008; 379:953–65.

    Article  PubMed  CAS  Google Scholar 

  80. von Ossowski I, Eaton JT, Czjzek M et al. Protein disorder: conformational distribution of the flexible linker in a chimeric double cellulase. Biophys J 2005; 88:2823–32.

    Article  Google Scholar 

  81. Lindner RA, Carver JA, Ehrnsperger M et al. Mouse Hsp25, a small shock protein. The role of its C-terminal extension in oligomerization and chaperone action. Eur J Biochem 2000; 267:1923–32.

    Article  PubMed  CAS  Google Scholar 

  82. Schwarz-Linek U, Pilka ES, Pickford AR et al. High affinity streptococcal binding to human fibronectin requires specific recognition of sequential F1 modules. J Biol Chem 2004; 279:39017–25.

    Article  PubMed  CAS  Google Scholar 

  83. Gill G, Pascal E, Tseng ZH et al. A glutamine-rich hydrophobic patch in transcription factor Sp1 contacts the dTAFII110 component of the Drosophila TFIID complex and mediates transcriptional activation. Proc Natl Acad Sci USA 1994; 91(1):192–96.

    Article  PubMed  CAS  Google Scholar 

  84. Lee GM, Pufall MA, Meeker CA et al. The affinity of Ets-1 for DNA is modulated by phosphorylation through transient interactions of an unstructured region. J Mol Biol 2008; 382:1014–30.

    Article  PubMed  CAS  Google Scholar 

  85. Pometun MS, Chekmenev EY, Wittebort RJ. Quantitative observation of backbone disorder in native elastin. J Biol Chem 2004; 279(9):7982–87.

    Article  PubMed  CAS  Google Scholar 

  86. Ross ED, Baxa U, Wickner RB. Scrambled prion domains form prions and amyloid. Mol Cell Biol 2004; 24(16):7206–13.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Peter Tompa .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

Fuxreiter, M., Tompa, P. (2012). Fuzzy Complexes: A More Stochastic View of Protein Function. In: Fuxreiter, M., Tompa, P. (eds) Fuzziness. Advances in Experimental Medicine and Biology, vol 725. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0659-4_1

Download citation

Publish with us

Policies and ethics