Advertisement

Conformational Characterization of Intrinsically Disordered Proteins and Its Biological Significance

  • Elise Delaforge
  • Tiago N. Cordeiro
  • Pau Bernadó
  • Nathalie Sibille
Reference work entry

Abstract

Intrinsically disordered proteins (IDPs) perform a large variety of functions that are crucial for signaling, cell regulation, and homeostasis. Functions performed by IDPs are complementary to those executed by their globular counterparts demonstrating that the biophysical properties of disordered proteins dictate their functional mechanisms. Conformational plasticity, large solvent accessibility, and transient structuration are inherent characteristics of IDPs that are ideal to modulate partner recognition in signaling processes. As a consequence, the characterization of the structural features of IDPs in their free state and in complex with the relevant biological partners is crucial to reveal the molecular basis of signaling and cell regulation. Nuclear magnetic resonance (NMR) is the only structural biology technique to derive structural and dynamic information of IDPs at the residue level. NMR can probe the conformational landscape of IDPs and monitor the changes exerted by environmental conditions, posttranslational modifications, or recognition events. Through multiple parameters, NMR is a rich source of structural and dynamic information covering residue-specific conformational and long-range intramolecular interactions. Additionally, NMR data can be complemented by information obtained from other biophysical techniques such as small-angle X-ray scattering (SAXS) that probe the overall properties of the protein in solution. This chapter aims at describing the main technical and conceptual developments that have enabled NMR to decipher the structural basis of the biological role of IDPs in multitude of crucial biological processes.

Keywords

Intrinsically disordered proteins Conformational ensemble Disordered complexes Integrative methods 

Notes

Acknowledgments

Financial support by the ERC-CoG (chemREPEAT – 648030) is gratefully acknowledged. The CBS is a member of the France-BioImaging (FBI) and the French Infrastructure for Integrated Structural Biology (FRISBI), 2 national infrastructures supported by the French National Research Agency (ANR-10-INSB-04-01 and ANR-10-INBS-05, respectively).

References

  1. 1.
    Ward JJ, Sodhi JS, Mcguffin LJ, Buxton BF, Jones DT. Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J Mol. Biol. 2004;337,635–45.CrossRefGoogle Scholar
  2. 2.
    Habchi J, Tompa P, Longhi S, Uversky VN. Introducing protein intrinsic disorder. Chem Rev [Internet]. 2014;114:6561–88. Available from:  https://doi.org/10.1021/cr400514hCrossRefGoogle Scholar
  3. 3.
    Tompa P, Schad E, Tantos A, Kalmar L. Intrinsically disordered proteins: emerging interaction specialists. Curr Opin Struct Biol. 2015;35:49–59.CrossRefGoogle Scholar
  4. 4.
    Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN. Flexible nets. The roles of intrinsic disorder in protein interaction networks. FEBS J. 2005;272:5129–48.CrossRefGoogle Scholar
  5. 5.
    Uversky VN, Oldfield CJ, Dunker AK. Intrinsically disordered proteins in human diseases: introducing the D2 concept. Annu Rev Biophys. 2008;37:215–46.CrossRefGoogle Scholar
  6. 6.
    Landrieu I, Lacosse L, Leroy A, Wieruszeski J-M, Trivelli X, Sillen A, et al. NMR analysis of a Tau phosphorylation pattern. J Am Chem Soc [Internet]. 2006;128:3575–83. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16536530CrossRefGoogle Scholar
  7. 7.
    Sugase K, Dyson HJ, Wright PE. Mechanism of coupled folding and binding of an intrinsically disordered protein. Nature. 2007;447:1021–5.CrossRefGoogle Scholar
  8. 8.
    Sibille N, Huvent I, Fauquant C, Verdegem D, Amniai L, Leroy A, et al. Structural characterization by nuclear magnetic resonance of the impact of phosphorylation in the proline-rich region of the disordered Tau protein. Proteins. 2012;80:454–62.CrossRefGoogle Scholar
  9. 9.
    Dyson HJ, Wright PE. Unfolded proteins and protein folding studied by NMR. Chem Rev. 2004;104:3607–22.CrossRefGoogle Scholar
  10. 10.
    Yao X, Becker S, Zweckstetter M. A six-dimensional alpha proton detection-based APSY experiment for backbone assignment of intrinsically disordered proteins. J Biomol NMR. 2014;60:231–40.CrossRefGoogle Scholar
  11. 11.
    Mark W-Y, Liao JCC, Lu Y, Ayed A, Laister R, Szymczyna B, et al. Characterization of segments from the central region of BRCA1: an intrinsically disordered scaffold for multiple protein-protein and protein-DNA interactions? J Mol Biol. 2005;345:275–87.CrossRefGoogle Scholar
  12. 12.
    Uversky VN, Gillespie JR, Fink AL. Why are “natively unfolded” proteins unstructured under physiologic conditions? Proteins. 2000;41:415–27.CrossRefGoogle Scholar
  13. 13.
    Mäntylahti S, Hellman M, Permi P. Extension of the HA-detection based approach: (HCA)CON(CA)H and (HCA)NCO(CA)H experiments for the main-chain assignment of intrinsically disordered proteins. J Biomol NMR [Internet]. 2011 [cited 2012 Oct 12];49:99–109. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21259120CrossRefGoogle Scholar
  14. 14.
    De Biasio A, Ibáñez De Opakua A, Cordeiro TN, Villate M, Merino N, Sibille N, et al. P15PAF is an intrinsically disordered protein with nonrandom structural preferences at sites of interaction with other proteins. Biophys J. 2014;106:865–74.CrossRefGoogle Scholar
  15. 15.
    Bermel W, Bertini I, Felli IC, Lee Y-M, Luchinat C, Pierattelli R. Protonless NMR experiments for sequence-specific assignment of backbone nuclei in unfolded proteins. J Am Chem Soc. 2006;128:3918–9.CrossRefGoogle Scholar
  16. 16.
    Jorda J, Kajava AV. Protein homorepeats sequences, structures, evolution, and functions. Adv Protein Chem Struct Biol. 2010;79:59–88.CrossRefGoogle Scholar
  17. 17.
    Eftekharzadeh B, Piai A, Chiesa G, Mungianu D, Garcia J, Pierattelli R, et al. Sequence context influences the structure and aggregation behavior of a PolyQ Tract. Biophys J. 2016;110:2361–6.CrossRefGoogle Scholar
  18. 18.
    Kim S, Wu K-P, Baum J. Fast hydrogen exchange affects 15 N relaxation measurements in intrinsically disordered proteins. J Biomol NMR. 2013;55:249–56.CrossRefGoogle Scholar
  19. 19.
    Baran MC, Huang YJ, Moseley HNB, Montelione GT. Automated analysis of protein NMR assignments and structures. Chem Rev. 2004;104:3541–56.CrossRefGoogle Scholar
  20. 20.
    Narayanan RL, Durr UHN, Bibow S, Biernat J, Mandelkow E, Zweckstetter M. Automatic assignment of the intrinsically disordered protein Tau with 441-residues. J Am Chem Soc. 2010;132:11906–7.CrossRefGoogle Scholar
  21. 21.
    Wishart DS, Sykes BD, Richards FM. The chemical shift index: a fast and simple method for the assignment of protein secondary structure through NMR spectroscopy. Biochemistry. 1992;31:1647–51.CrossRefGoogle Scholar
  22. 22.
    Wishart DS, Bigam CG, Holm A, Hodges RS, Sykes BD. 1H, 13C and 15N random coil NMR chemical shifts of the common amino acids. I. Investigations of nearest-neighbor effects. J Biomol NMR. 1995;5:67–81.CrossRefGoogle Scholar
  23. 23.
    Schwarzinger S, Kroon GJ, Foss TR, Chung J, Wright PE, Dyson HJ. Sequence-dependent correction of random coil NMR chemical shifts. J Am Chem Soc [Internet]. 2001;123:2970–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11457007CrossRefGoogle Scholar
  24. 24.
    Kjaergaard M, Poulsen FM. Sequence correction of random coil chemical shifts: correlation between neighbor correction factors and changes in the Ramachandran distribution. J Biomol NMR [Internet]. 2011 [cited 2012 Oct 12];50:157–65. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21604143CrossRefGoogle Scholar
  25. 25.
    Tamiola K, Acar B, Mulder FAA. Sequence specific random coil chemical shifts of intrinsically disordered proteins. J Am Chem Soc. 2010;132:18000–3.CrossRefGoogle Scholar
  26. 26.
    Zhang H, Neal S, Wishart DS. RefDB: a database of uniformly referenced protein chemical shifts. J Biomol NMR. 2003;25:173–95.CrossRefGoogle Scholar
  27. 27.
    Marsh JA, Singh VK, Jia Z, Forman-Kay JD. Sensitivity of secondary structure propensities to sequence differences between alpha- and gamma-synuclein: implications for fibrillation. Protein Sci A Publ Protein Soc. 2006;15:2795–804.CrossRefGoogle Scholar
  28. 28.
    Theillet F-X, Smet-Nocca C, Liokatis S, Thongwichian R, Kosten J, Yoon M-K, et al. Cell signaling, post-translational protein modifications and NMR spectroscopy. J Biomol NMR. 2012;54:217–36.CrossRefGoogle Scholar
  29. 29.
    Cordier F, Chaffotte A, Terrien E, Prehaud C, Theillet F-X, Delepierre M, et al. Ordered phosphorylation events in two independent cascades of the PTEN C-tail revealed by NMR. J Am Chem Soc. 2012;134:20533–43.CrossRefGoogle Scholar
  30. 30.
    Baker JMR, Hudson RP, Kanelis V, Choy W-Y, Thibodeau PH, Thomas PJ, et al. CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices. Nat Struct Mol Biol. 2007;14:738–45.CrossRefGoogle Scholar
  31. 31.
    Okuda M, Nishimura Y. Real-time and simultaneous monitoring of the phosphorylation and enhanced interaction of p53 and XPC acidic domains with the TFIIH p62 subunit. Oncogenesis [Internet]. 2015;4:e150. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753521/CrossRefGoogle Scholar
  32. 32.
    Karplus M. Vicinal proton coupling in nuclear magnetic resonance. J Am Chem Soc. 1963;85:2870–1.CrossRefGoogle Scholar
  33. 33.
    Vögeli B, Ying J, Grishaev A, Bax A. Limits on variations in protein backbone dynamics from precise measurements of scalar couplings. J Am Chem Soc. 2007;129:9377–85.CrossRefGoogle Scholar
  34. 34.
    Vuister GW, Bax A. Quantitative J correlation: a new approach for measuring homonuclear three-bond J(HNH.alpha.) coupling constants in 15N-enriched proteins. J Am Chem Soc [Internet]. 1993;115:7772–7. Available from:  https://doi.org/10.1021/ja00070a024
  35. 35.
    Roche J, Ying J, Bax A. Accurate measurement of (3)J(HNHalpha) couplings in small or disordered proteins from WATERGATE-optimized TROSY spectra. J Biomol NMR. 2016;64:1–7.CrossRefGoogle Scholar
  36. 36.
    Oh K-I, Lee K-K, Park E-K, Jung Y, Hwang G-S, Cho M. A comprehensive library of blocked dipeptides reveals intrinsic backbone conformational propensities of unfolded proteins. Proteins. 2012;80:977–90.CrossRefGoogle Scholar
  37. 37.
    Plaxco KW, Morton CJ, Grimshaw SB, Jones JA, Pitkeathly M, Campbell ID, et al. The effects of guanidine hydrochloride on the “random coil” conformations and NMR chemical shifts of the peptide series GGXGG. J Biomol NMR [Internet]. 1997;10:221–30. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20700831
  38. 38.
    Smith LJ, Bolin KA, Schwalbe H, MacArthur MW, Thornton JM, Dobson CM. Analysis of main chain torsion angles in proteins: prediction of NMR coupling constants for native and random coil conformations. J Mol Biol. 1996;255:494–506.CrossRefGoogle Scholar
  39. 39.
    Tjandra N, Bax A. Direct measurement of distances and angles in biomolecules by NMR in a dilute liquid crystalline medium. Science. 1997;278:1111–4.CrossRefGoogle Scholar
  40. 40.
    Prestegard JH, Bougault CM, Kishore AI. Residual dipolar couplings in structure determination of biomolecules. Chem Rev. 2004;104:3519–40.CrossRefGoogle Scholar
  41. 41.
    Huang J, Ozenne V, Jensen MR, Blackledge M. Direct prediction of NMR residual dipolar couplings from the primary sequence of unfolded proteins. Angew Chem Int Ed Eng. 2013;52:687–90.CrossRefGoogle Scholar
  42. 42.
    Kosol S, Contreras-Martos S, Cedeño C, Tompa P. Structural Characterization of Intrinsically Disordered Proteins by NMR Spectroscopy. Molecules. 2013;18:10802–28.CrossRefGoogle Scholar
  43. 43.
    Louhivuori M, Pääkkönen K, Fredriksson K, Permi P, Lounila J, Annila A. On the origin of residual dipolar couplings from denatured proteins. J Am Chem Soc [Internet]. 2003;125:15647–50. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14664613CrossRefGoogle Scholar
  44. 44.
    Jensen MR, Houben K, Lescop E, Blanchard L, Ruigrok RWH, Blackledge M. Quantitative conformational analysis of partially folded proteins from residual dipolar couplings: application to the molecular recognition element of Sendai virus nucleoprotein. J Am Chem Soc. 2008;130:8055–61.CrossRefGoogle Scholar
  45. 45.
    Bernado P, Bertoncini CW, Griesinger C, Zweckstetter M, Blackledge M. Defining long-range order and local disorder in native alpha-synuclein using residual dipolar couplings. J Am Chem Soc. 2005;127:17968–9.CrossRefGoogle Scholar
  46. 46.
    Prestegard JH, Kishore AI. Partial alignment of biomolecules: an aid to NMR characterization. Curr Opin Chem Biol [Internet]. 2001;5:584–90. Available from: http://www.sciencedirect.com/science/article/pii/S1367593100002477CrossRefGoogle Scholar
  47. 47.
    Korzhnev DM, Billeter M, Arseniev AS, Orekhov VY. NMR studies of Brownian tumbling and internal motions in proteins. Prog Nucl Magn Reson Spectrosc [Internet]. 2001;38:197–266. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0079656500000285CrossRefGoogle Scholar
  48. 48.
    Bracken C. NMR spin relaxation methods for characterization of disorder and folding in proteins. J Mol Graph Model. 2001;19:3–12.CrossRefGoogle Scholar
  49. 49.
    Peng JW, Wagner G. Mapping of the spectral densities of N-H bond motions in eglin c using heteronuclear relaxation experiments. Biochemistry [Internet]. 1992;31:8571–86. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1390643CrossRefGoogle Scholar
  50. 50.
    Abyzov A, Salvi N, Schneider R, Maurin D, Ruigrok RWH, Jensen MR, et al. Identification of dynamic modes in an intrinsically disordered protein using temperature-dependent NMR relaxation. J Am Chem Soc. 2016;138:6240–51.CrossRefGoogle Scholar
  51. 51.
    Uversky VN. Seven lessons from one IDP structural analysis. Structure [Internet]. 2010 [cited 2016 Feb 26];18:1069–71. Available from: http://www.sciencedirect.com/science/article/pii/S0969212610002753CrossRefGoogle Scholar
  52. 52.
    Gillespie JR, Shortle D. Characterization of long-range structure in the denatured state of staphylococcal nuclease. I. Paramagnetic relaxation enhancement by nitroxide spin labels. J Mol Biol [Internet]. 1997;268:158–69. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9149149CrossRefGoogle Scholar
  53. 53.
    Yagi H, Pilla KB, Maleckis A, Graham B, Huber T, Otting G. Three-dimensional protein fold determination from backbone amide pseudocontact shifts generated by lanthanide tags at multiple sites. Structure (London, Engl. 1993). 2013;21:883–90.CrossRefGoogle Scholar
  54. 54.
    Berliner LJ, Grunwald J, Hankovszky HO, Hideg K. A novel reversible thiol-specific spin label: papain active site labeling and inhibition. Anal Biochem. 1982;119:450–5.CrossRefGoogle Scholar
  55. 55.
    Ramos A, Varani G. A new method to detect long-range protein – RNA contacts: NMR detection of electron – proton relaxation induced by nitroxide spin-labeled RNA. J Am Chem Soc [Internet]. 1998;120:10992–3. Available from:  https://doi.org/10.1021/ja982496eCrossRefGoogle Scholar
  56. 56.
    Jensen MR, Zweckstetter M, Huang J, Blackledge M. Exploring free-energy landscapes of intrinsically disordered proteins at atomic resolution using NMR spectroscopy. Chem Rev. 2014;114:6632–60.CrossRefGoogle Scholar
  57. 57.
    Jensen MR, Ruigrok RWH, Blackledge M. Describing intrinsically disordered proteins at atomic resolution by NMR. Curr Opin Struct Biol. 2013;23:426–35.CrossRefGoogle Scholar
  58. 58.
    Kruschel D, Zagrovic B. Conformational averaging in structural biology: issues, challenges and computational solutions. Mol BioSyst. 2009;5:1606–16.CrossRefGoogle Scholar
  59. 59.
    Eliezer D. Biophysical characterization of intrinsically disordered proteins. Curr Opin Struct Biol. 2009;19:23–30.CrossRefGoogle Scholar
  60. 60.
    Vendruscolo M. Determination of conformationally heterogeneous states of proteins. Curr Opin Struct Biol. 2007;17:15–20.CrossRefGoogle Scholar
  61. 61.
    Robustelli P, Stafford KA, Palmer 3rd AG. Interpreting protein structural dynamics from NMR chemical shifts. J Am Chem Soc. 2012;134:6365–74.CrossRefGoogle Scholar
  62. 62.
    Allison JR, Varnai P, Dobson CM, Vendruscolo M. Determination of the free energy landscape of alpha-synuclein using spin label nuclear magnetic resonance measurements. J Am Chem Soc. 2009;131:18314–26.CrossRefGoogle Scholar
  63. 63.
    Ganguly D, Chen J. Structural interpretation of paramagnetic relaxation enhancement-derived distances for disordered protein states. J Mol Biol. 2009;390:467–77.CrossRefGoogle Scholar
  64. 64.
    Esteban-Martin S, Fenwick RB, Salvatella X. Refinement of ensembles describing unstructured proteins using NMR residual dipolar couplings. J Am Chem Soc. 2010;132:4626–32.CrossRefGoogle Scholar
  65. 65.
    Huang J, Grzesiek S. Ensemble calculations of unstructured proteins constrained by RDC and PRE data: a case study of urea-denatured ubiquitin. J Am Chem Soc. 2010;132:694–705.CrossRefGoogle Scholar
  66. 66.
    Wu K-P, Weinstock DS, Narayanan C, Levy RM, Baum J. Structural reorganization of alpha-synuclein at low pH observed by NMR and REMD simulations. J Mol Biol. 2009;391:784–96.CrossRefGoogle Scholar
  67. 67.
    Cavalli A, Camilloni C, Vendruscolo M. Molecular dynamics simulations with replica-averaged structural restraints generate structural ensembles according to the maximum entropy principle. J Chem Phys. 2013;138:94112.CrossRefGoogle Scholar
  68. 68.
    Henriques J, Cragnell C, Skepo M. Molecular dynamics simulations of intrinsically disordered proteins: force field evaluation and comparison with experiment. J Chem Theory Comput. 2015;11:3420–31.CrossRefGoogle Scholar
  69. 69.
    Mercadante D, Milles S, Fuertes G, Svergun DI, Lemke EA, Grater F. Kirkwood-buff approach rescues overcollapse of a disordered protein in canonical protein force fields. J Phys Chem B. 2015;119:7975–84.CrossRefGoogle Scholar
  70. 70.
    Mukrasch MD, Markwick P, Biernat J, von Bergen M, Bernado P, Griesinger C, et al. Highly populated turn conformations in natively unfolded tau protein identified from residual dipolar couplings and molecular simulation. J Am Chem Soc. 2007;129:5235–43.CrossRefGoogle Scholar
  71. 71.
    Fisher CK, Huang A, Stultz CM. Modeling intrinsically disordered proteins with bayesian statistics. J Am Chem Soc. 2010;132:14919–27.CrossRefGoogle Scholar
  72. 72.
    Fitzkee NC, Fleming PJ, Rose GD. The protein coil library: a structural database of nonhelix, nonstrand fragments derived from the PDB. Proteins. 2005;58:852–4.CrossRefGoogle Scholar
  73. 73.
    Jha AK, Colubri A, Freed KF, Sosnick TR. Statistical coil model of the unfolded state: resolving the reconciliation problem. Proc Natl Acad Sci U S A. 2005;102:13099–104.CrossRefGoogle Scholar
  74. 74.
    Bernado P, Blanchard L, Timmins P, Marion D, Ruigrok RWH, Blackledge M. A structural model for unfolded proteins from residual dipolar couplings and small-angle x-ray scattering. Proc Natl Acad Sci U S A. 2005;102:17002–7.CrossRefGoogle Scholar
  75. 75.
    Ozenne V, Bauer F, Salmon L, Huang J-R, Jensen MR, Segard S, et al. Flexible-meccano: a tool for the generation of explicit ensemble descriptions of intrinsically disordered proteins and their associated experimental observables. Bioinformatics. 2012;28:1463–70.CrossRefGoogle Scholar
  76. 76.
    Wells M, Tidow H, Rutherford TJ, Markwick P, Jensen MR, Mylonas E, et al. Structure of tumor suppressor p53 and its intrinsically disordered N-terminal transactivation domain. Proc Natl Acad Sci U S A. 2008;105:5762–7.CrossRefGoogle Scholar
  77. 77.
    Perez Y, Gairi M, Pons M, Bernado P. Structural characterization of the natively unfolded N-terminal domain of human c-Src kinase: insights into the role of phosphorylation of the unique domain. J Mol Biol. 2009;391:136–48.CrossRefGoogle Scholar
  78. 78.
    Choy WY, Forman-Kay JD. Calculation of ensembles of structures representing the unfolded state of an SH3 domain. J Mol Biol. 2001;308:1011–32.CrossRefGoogle Scholar
  79. 79.
    Krzeminski M, Marsh JA, Neale C, Choy W-Y, Forman-Kay JD. Characterization of disordered proteins with ENSEMBLE. Bioinformatics. 2013;29:398–9.CrossRefGoogle Scholar
  80. 80.
    Salmon L, Nodet G, Ozenne V, Yin G, Jensen MR, Zweckstetter M, et al. NMR characterization of long-range order in intrinsically disordered proteins. J Am Chem Soc. 2010;132:8407–18.CrossRefGoogle Scholar
  81. 81.
    Nodet G, Salmon L, Ozenne V, Meier S, Jensen MR, Blackledge M. Quantitative description of backbone conformational sampling of unfolded proteins at amino acid resolution from NMR residual dipolar couplings. J Am Chem Soc. 2009;131:17908–18.CrossRefGoogle Scholar
  82. 82.
    Ozenne V, Schneider R, Yao M, Huang J, Salmon L, Zweckstetter M, et al. Mapping the potential energy landscape of intrinsically disordered proteins at amino acid resolution. J Am Chem Soc. 2012;134:15138–48.CrossRefGoogle Scholar
  83. 83.
    Sibille N, Bernadó P. Structural characterization of intrinsically disordered proteins by the combined use of NMR and SAXS. Biochem. Soc Trans [Internet]. 2012;40:955–62. Available from: http://www.biochemsoctrans.org/bst/040/0955/bst0400955.htmCrossRefGoogle Scholar
  84. 84.
    Cordeiro TN, Herranz-Trillo F, Urbanek A, Estana A, Cortes J, Sibille N, et al. Small-angle scattering studies of intrinsically disordered proteins and their complexes. Curr Opin Struct Biol. 2016;42:15–23.CrossRefGoogle Scholar
  85. 85.
    Delaforge E, Milles S, Bouvignies G, Bouvier D, Boivin S, Salvi N, et al. large-scale conformational dynamics control H5N1 influenza polymerase PB2 binding to importin alpha. J Am Chem Soc. 2015;137:15122–34.CrossRefGoogle Scholar
  86. 86.
    Bibow S, Ozenne V, Biernat J, Blackledge M, Mandelkow E, Zweckstetter M. Structural impact of proline-directed pseudophosphorylation at AT8, AT100, and PHF1 epitopes on 441-residue tau. J Am Chem Soc. 2011;133:15842–5.CrossRefGoogle Scholar
  87. 87.
    Schwalbe M, Ozenne V, Bibow S, Jaremko M, Jaremko L, Gajda M, et al. Predictive atomic resolution descriptions of intrinsically disordered hTau40 and α-Synuclein in solution from {NMR} and small angle scattering. Structure [Internet]. 2014;22:238–49. Available from: http://www.sciencedirect.com/science/article/pii/S096921261300436XCrossRefGoogle Scholar
  88. 88.
    Fisher CK, Stultz CM. Constructing ensembles for intrinsically disordered proteins. Curr Opin Struct Biol. 2011;21:426–31.CrossRefGoogle Scholar
  89. 89.
    Ullman O, Fisher CK, Stultz CM. Explaining the structural plasticity of alpha-synuclein. J Am Chem Soc. 2011;133:19536–46.CrossRefGoogle Scholar
  90. 90.
    Varadi M, Kosol S, Lebrun P, Valentini E, Blackledge M, Dunker AK, et al. pE-DB: a database of structural ensembles of intrinsically disordered and of unfolded proteins. Nucleic Acids Res. 2014;42:D326–35.CrossRefGoogle Scholar
  91. 91.
    De Biasio A, de Opakua AI, Mortuza GB, Molina R, Cordeiro TN, Castillo F, et al. Structure of p15(PAF)-PCNA complex and implications for clamp sliding during DNA replication and repair. Nat Commun. 2015;6:6439.CrossRefGoogle Scholar
  92. 92.
    Cordeiro TN, Chen P-C, De Biasio A, Sibille N, Blanco FJ, Hub JS, et al. Disentangling polydispersity in the PCNA-p15PAF complex, a disordered, transient and multivalent macromolecular assembly. Nucleic Acids Res. 2016. PMID: 27913731  https://doi.org/10.1093/nar/gkw1183
  93. 93.
    Wright PE, Dyson HJ. Linking folding and binding. Curr Opin Struct Biol. 2009;19:31–8.CrossRefGoogle Scholar
  94. 94.
    Arai M, Sugase K, Dyson HJ, Wright PE. Conformational propensities of intrinsically disordered proteins influence the mechanism of binding and folding. Proc Natl Acad Sci U S A. 2015;112:9614–9.CrossRefGoogle Scholar
  95. 95.
    Schneider R, Maurin D, Communie G, Kragelj J, Hansen DF, Ruigrok RWH, et al. Visualizing the molecular recognition trajectory of an intrinsically disordered protein using multinuclear relaxation dispersion NMR. J Am Chem Soc. 2015;137:1220–9.CrossRefGoogle Scholar
  96. 96.
    Janin J, Sternberg MJE. Protein flexibility, not disorder, is intrinsic to molecular recognition. F1000 Biol Rep. 2013;5:2.CrossRefGoogle Scholar
  97. 97.
    Miskei M, Antal C, Fuxreiter M. FuzDB: database of fuzzy complexes, a tool to develop stochastic structure-function relationships for protein complexes and higher-order assemblies. Nucleic Acids Res. 2017;45(D1):D228–D235.CrossRefGoogle Scholar
  98. 98.
    Didry D, Cantrelle F-X, Husson C, Roblin P, Moorthy AME, Perez J, et al. How a single residue in individual beta-thymosin/WH2 domains controls their functions in actin assembly. EMBO J. 2012;31:1000–13.CrossRefGoogle Scholar
  99. 99.
    Mittag T, Orlicky S, Choy W-Y, Tang X, Lin H, Sicheri F, et al. Dynamic equilibrium engagement of a polyvalent ligand with a single-site receptor. Proc Natl Acad Sci U S A. 2008;105:17772–7.CrossRefGoogle Scholar
  100. 100.
    Nash P, Tang X, Orlicky S, Chen Q, Gertler FB, Mendenhall MD, et al. Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication. Nature. 2001;414:514–21.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Elise Delaforge
    • 1
  • Tiago N. Cordeiro
    • 1
    • 2
  • Pau Bernadó
    • 1
  • Nathalie Sibille
    • 1
  1. 1.Centre de Biochimie Structurale, CNRS UMR 5048 – INSERM U1054Université de MontpellierMontpellierFrance
  2. 2.X-ray and Neutron ScienceNiels Bohr InstituteCopenhagenDenmark

Personalised recommendations