Home LiteratureArticle Details
PMID: 19157855 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Linking folding and binding.

Current opinion in structural biology ·Vol. 19 ·No. 1 ·2009-02-00 ·Pages 31-8

Wright PE, Dyson HJ

Abstract

Many cellular proteins are intrinsically disordered and undergo folding, in whole or in part, upon binding to their physiological targets. The past few years have seen an exponential increase in papers describing characterization of intrinsically disordered proteins, both free and bound to targets. Although NMR spectroscopy remains the favored tool, a number of new biophysical techniques are proving exceptionally useful in defining the limits of the conformational ensembles. Advances have been made in prediction of the recognition elements in disordered proteins, in elucidating the kinetics and mechanism of the coupled folding and binding process, and in understanding the role of post-translational modifications in tuning the biological response. Here we review these and other recent advances that are providing new insights into the conformational propensities and interactions of intrinsically disordered proteins and are beginning to reveal general principles underlying their biological functions.

MeSH Terms
Animals Binding Sites Databases, Protein Humans Kinetics Models, Molecular Phosphorylation Protein Conformation Protein Folding Proteins/chemistry,metabolism Signal Transduction
Chemicals
Proteins
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Wright Peter E
Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States. [email protected]
Dyson H Jane
References (63)
63 references, click to expand
  1. Intrinsically disordered gamma-subunit of cGMP phosphodiesterase encodes functionally relevant transient secondary and tertiary structure.
    Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1505-10 PMID: 18230733
  2. Intrinsic disorder as a mechanism to optimize allosteric coupling in proteins.
    Proc Natl Acad Sci U S A. 2007 May 15;104(20):8311-5 PMID: 17494761
  3. Structure of tumor suppressor p53 and its intrinsically disordered N-terminal transactivation domain.
    Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5762-7 PMID: 18391200
  4. Variable control of Ets-1 DNA binding by multiple phosphates in an unstructured region.
    Science. 2005 Jul 1;309(5731):142-5 PMID: 15994560
  5. Molecular principles of the interactions of disordered proteins.
    J Mol Biol. 2007 Sep 14;372(2):549-61 PMID: 17681540
  6. An entropic mechanism to generate highly cooperative and specific binding from protein phosphorylations.
    Curr Biol. 2006 Nov 7;16(21):2150-5 PMID: 17084700
  7. Structural basis for cooperative transcription factor binding to the CBP coactivator.
    J Mol Biol. 2006 Feb 3;355(5):1005-13 PMID: 16253272
  8. Assessing induced folding of an intrinsically disordered protein by site-directed spin-labeling electron paramagnetic resonance spectroscopy.
    J Phys Chem B. 2006 Oct 19;110(41):20596-608 PMID: 17034249
  9. Close encounters: why unstructured, polymeric domains can increase rates of specific macromolecular association.
    Trends Biochem Sci. 1993 May;18(5):181-6 PMID: 8328018
  10. Exploring the mechanism of flexible biomolecular recognition with single molecule dynamics.
    Phys Rev Lett. 2007 Mar 23;98(12):128105 PMID: 17501161
  11. Conformational preferences in the Ser133-phosphorylated and non-phosphorylated forms of the kinase inducible transactivation domain of CREB.
    FEBS Lett. 1998 Jul 3;430(3):317-22 PMID: 9688563
  12. Flexible nets: disorder and induced fit in the associations of p53 and 14-3-3 with their partners.
    BMC Genomics. 2008;9 Suppl 1:S1 PMID: 18366598
  13. Disorder in a target for the smad2 mad homology 2 domain and its implications for binding and specificity.
    J Biol Chem. 2004 Sep 24;279(39):40707-14 PMID: 15231848
  14. Preformed structural elements feature in partner recognition by intrinsically unstructured proteins.
    J Mol Biol. 2004 May 14;338(5):1015-26 PMID: 15111064
  15. Mechanism of coupled folding and binding of an intrinsically disordered protein.
    Nature. 2007 Jun 21;447(7147):1021-5 PMID: 17522630
  16. Mechanism of induced folding: Both folding before binding and binding before folding can be realized in staphylococcal nuclease mutants.
    Proteins. 2008 Aug 15;72(3):837-47 PMID: 18260114
  17. 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. 2007 May;6(5):1899-916 PMID: 17391015
  18. Intrinsically unstructured proteins and their functions.
    Nat Rev Mol Cell Biol. 2005 Mar;6(3):197-208 PMID: 15738986
  19. Probing invisible, low-populated States of protein molecules by relaxation dispersion NMR spectroscopy: an application to protein folding.
    Acc Chem Res. 2008 Mar;41(3):442-51 PMID: 18275162
  20. Intrinsic disorder and functional proteomics.
    Biophys J. 2007 Mar 1;92(5):1439-56 PMID: 17158572
  21. Packing, specificity, and mutability at the binding interface between the p160 coactivator and CREB-binding protein.
    Protein Sci. 2004 Jan;13(1):203-10 PMID: 14691235
  22. Intrinsically disordered proteins display no preference for chaperone binding in vivo.
    PLoS Comput Biol. 2008 Mar 07;4(3):e1000017 PMID: 18369417
  23. Protein conformational transitions coupled to binding in molecular recognition of unstructured proteins: deciphering the effect of intermolecular interactions on computational structure prediction of the p27Kip1 protein bound to the cyclin A-cyclin-dependent kinase 2 complex.
    Proteins. 2005 Feb 15;58(3):706-16 PMID: 15609350
  24. Functional anthology of intrinsic disorder. 3. Ligands, post-translational modifications, and diseases associated with intrinsically disordered proteins.
    J Proteome Res. 2007 May;6(5):1917-32 PMID: 17391016
  25. Visualization of intrinsically disordered regions of proteins by high-speed atomic force microscopy.
    Chemphyschem. 2008 Sep 15;9(13):1859-66 PMID: 18698566
  26. Structural characterization of flexible proteins using small-angle X-ray scattering.
    J Am Chem Soc. 2007 May 2;129(17):5656-64 PMID: 17411046
  27. Elucidation of the protein folding landscape by NMR.
    Methods Enzymol. 2005;394:299-321 PMID: 15808225
  28. Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm.
    J Mol Biol. 1999 Oct 22;293(2):321-31 PMID: 10550212
  29. Speeding molecular recognition by using the folding funnel: the fly-casting mechanism.
    Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):8868-73 PMID: 10908673
  30. Delineation of protein structure classes from multivariate analysis of protein Raman optical activity data.
    J Mol Biol. 2006 Oct 13;363(1):19-26 PMID: 16962609
  31. Thermodynamics of beta-catenin-ligand interactions: the roles of the N- and C-terminal tails in modulating binding affinity.
    J Biol Chem. 2006 Jan 13;281(2):1027-38 PMID: 16293619
  32. FlgM gains structure in living cells.
    Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12681-4 PMID: 12271132
  33. Molecular mimicry enables competitive recruitment by a natively disordered protein.
    J Am Chem Soc. 2007 Apr 18;129(15):4800-7 PMID: 17375930
  34. Phosphorylation-induced transient intrinsic structure in the kinase-inducible domain of CREB facilitates its recognition by the KIX domain of CBP.
    Proteins. 2006 Aug 15;64(3):749-57 PMID: 16761278
  35. Binding-induced folding of a natively unstructured transcription factor.
    PLoS Comput Biol. 2008 Apr 11;4(4):e1000060 PMID: 18404207
  36. Coupling of folding and binding for unstructured proteins.
    Curr Opin Struct Biol. 2002 Feb;12(1):54-60 PMID: 11839490
  37. A natively unfolded yeast prion monomer adopts an ensemble of collapsed and rapidly fluctuating structures.
    Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2649-54 PMID: 17299036
  38. Protein-protein interaction through beta-strand addition.
    Trends Biochem Sci. 2006 Aug;31(8):436-44 PMID: 16828554
  39. Fly-casting in protein-DNA binding: frustration between protein folding and electrostatics facilitates target recognition.
    J Am Chem Soc. 2007 Jan 31;129(4):738-9 PMID: 17243791
  40. Polyelectrostatic interactions of disordered ligands suggest a physical basis for ultrasensitivity.
    Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9650-5 PMID: 17522259
  41. The importance of intrinsic disorder for protein phosphorylation.
    Nucleic Acids Res. 2004 Feb 11;32(3):1037-49 PMID: 14960716
  42. Crystal structure of IRF-3 in complex with CBP.
    Structure. 2005 Sep;13(9):1269-77 PMID: 16154084
  43. 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. 2008 May 21;130(20):6310-1 PMID: 18419123
  44. The effects of conformational heterogeneity on the binding of the Notch intracellular domain to effector proteins: a case of biologically tuned disorder.
    Biochem Soc Trans. 2008 Apr;36(Pt 2):157-66 PMID: 18363556
  45. Mechanism of transcription factor recruitment by acidic activators.
    J Biol Chem. 2005 Jun 10;280(23):21779-84 PMID: 15826952
  46. Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions.
    J Proteome Res. 2007 May;6(5):1882-98 PMID: 17391014
  47. 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 Oct 15;93(21):11504-9 PMID: 8876165
  48. Tailoring relaxation dispersion experiments for fast-associating protein complexes.
    J Am Chem Soc. 2007 Nov 7;129(44):13406-7 PMID: 17935336
  49. Simulating disorder-order transitions in molecular recognition of unstructured proteins: where folding meets binding.
    Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5148-53 PMID: 12697905
  50. Structure of membrane-bound alpha-synuclein studied by site-directed spin labeling.
    Proc Natl Acad Sci U S A. 2004 Jun 1;101(22):8331-6 PMID: 15155902
  51. 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 Nov 1;277(44):42241-8 PMID: 12196545
  52. Flexible nets. The roles of intrinsic disorder in protein interaction networks.
    FEBS J. 2005 Oct;272(20):5129-48 PMID: 16218947
  53. A structural model for unfolded proteins from residual dipolar couplings and small-angle x-ray scattering.
    Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17002-7 PMID: 16284250
  54. Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators.
    Nature. 2002 Jan 31;415(6871):549-53 PMID: 11823864
  55. Intrinsically unstructured domains of Arf and Hdm2 form bimolecular oligomeric structures in vitro and in vivo.
    J Mol Biol. 2008 Dec 5;384(1):240-54 PMID: 18809412
  56. Kinetics of folding and binding of an intrinsically disordered protein: the inhibitor of yeast aspartic proteinase YPrA.
    J Am Chem Soc. 2008 Aug 27;130(34):11477-85 PMID: 18681437
  57. Analysis of molecular recognition features (MoRFs).
    J Mol Biol. 2006 Oct 6;362(5):1043-59 PMID: 16935303
  58. Functional consequences of preorganized helical structure in the intrinsically disordered cell-cycle inhibitor p27(Kip1).
    Biochemistry. 2002 Jan 22;41(3):752-9 PMID: 11790096
  59. CFTR regulatory region interacts with NBD1 predominantly via multiple transient helices.
    Nat Struct Mol Biol. 2007 Aug;14(8):738-45 PMID: 17660831
  60. Solution structure of the KIX domain of CBP bound to the transactivation domain of CREB: a model for activator:coactivator interactions.
    Cell. 1997 Dec 12;91(6):741-52 PMID: 9413984
  61. Mapping long-range interactions in alpha-synuclein using spin-label NMR and ensemble molecular dynamics simulations.
    J Am Chem Soc. 2005 Jan 19;127(2):476-7 PMID: 15643843
  62. Inferring function using patterns of native disorder in proteins.
    PLoS Comput Biol. 2007 Aug;3(8):e162 PMID: 17722973
  63. Structural disorder serves as a weak signal for intracellular protein degradation.
    Proteins. 2008 May 1;71(2):903-9 PMID: 18004785
Article Info
Journal
Current opinion in structural biology
Abbr.
Curr Opin Struct Biol
ISSN
1879-033X
DOI
10.1016/j.sbi.2008.12.003
Email
[email protected]
Published
2009-02-00
Epub
2009-00-20
Pages
31-8
Language
English
Region
England
NLM ID
9107784
PMCID
PMC2675572
Subset
IM
Grants
NIDDK NIH HHS · DK34909 · United States
NCI NIH HHS · R01 CA096865 · United States
NIDDK NIH HHS · R01 DK034909 · United States
NIGMS NIH HHS · P01 GM071862 · United States
NIGMS NIH HHS · GM57374 · United States
NCI NIH HHS · R01 CA096865-07 · United States
NCI NIH HHS · CA96865 · United States
NIDDK NIH HHS · R01 DK034909-23 · United States
External Links
PubMed source DOI: 10.1016/j.sbi.2008.12.003 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2