Fuzzy complex

NMR structure of the cyclin-dependent kinase inhibitor Sic1 with the ubiquitin ligase Cdc4 (grey). Out of the nine phosphorylation sites of Sic 1 (spheres) the contacts with T45 and S76 are shown (orange and blue).
The fuzzy linker region (shown by dotted line) of the Ultrabithorax transcription factor (orange) connects the homedomain with the Extradenticle homedomain (blue) (PDB code 1bi). Alternative splicing modulates the length of the fuzzy region and thus its DNA (grey) binding affinity. Other regulatory fuzzy regions of Ultrabithorax are also shown by dotted lines.

Fuzzy complexes are protein complexes, where structural ambiguity or multiplicity exists and is required for biological function.[1][2] Alteration, truncation or removal of conformationally ambiguous regions impacts the activity of the corresponding complex.[3][4][5] Fuzzy complexes are generally formed by intrinsically disordered proteins.[6][7] Structural multiplicity usually underlies functional multiplicity of protein complexes [8][9][10] following a fuzzy logic. Distinct binding modes of the nucleosome are also regarded as a special case of fuzziness.[11][12]

Historical background

For almost 50 years molecular biology was based on two dogmas: (i) equating biological function of the protein with a unique three-dimensional structure and (ii) assuming exquisite specificity in protein complexes. Specificity/selectivity is ensured by unambiguous set of interactions formed between the protein and its ligand (another protein, DNA, RNA or small molecule). Many protein complexes however, contain functionally important/critical regions, which remain highly dynamic in the complex or adopt different conformations.[13] This phenomenon is defined fuzziness. The most pertinent example is the cyclin-dependent kinase inhibitor Sic1, which binds to the SCF subunit of Cdc4 in a phosphorylation dependent manner.[14] No regular secondary structures are gained upon phosphorylation and the different phosphorylation sites interchange in the complex.[15]

Classification of fuzzy complexes

Structural ambiguity in protein complexes covers a wide spectrum.[1] In a polymorphic complex, the protein adopts two or more different conformations upon binding to the same partner, and these conformations can be resolved.[16] Clamp,[17] flanking [18][19] and random complexes [20][21] are dynamic, where ambiguous conformations interchange with each other and cannot be resolved. Interactions in fuzzy complexes are usually mediated by short motifs,.[22][23] Flanking regions are tolerant to sequence changes as long as the amino acid composition is maintained, for example in case of linker histone C-terminal domains [24] and H4 histone N-terminal domains.[25]

Regulatory pathways via fuzzy regions

Fuzzy regions modulate the conformational equilibrium [26] or flexibility [3][27] of the binding interface via transient interactions.[28] Dynamic regions can also compete with binding sites [29] or tether them to the target.[30] Modifications of fuzzy regions by further interactions,[8][31] or posttranslational modifications [32][33] impact binding affinity or specificity. Alternative splicing can modulate the length of fuzzy regions resulting in context-dependent binding (e.g. tissue-specificity) on the complex.[34][35][36] EGF/MAPK, TGF-β and WNT/Wingless signaling pathways employ tissue-specific fuzzy regions.

References

  1. 1 2 Tompa, P. & Fuxreiter, M. (Jan 2008) "Fuzzy complexes: polymorphism and structural disorder in protein-protein interactions". Trends Biochem Sci 33,(1): 2-8. PMID 18054235.
  2. ↑ Fuxreiter, M. & Tompa, P. (2011) Fuzziness: Structural Disorder in Protein Complexes Austin, New York.
  3. 1 2 Pufall, M.A., Lee, G.M., Nelson, M.L., Kang, H.S., Velyvis, A. et al. (Jul 1 2005) "Variable control of Ets-1 DNA binding by multiple phosphates in an unstructured region". Science 309,(5731): 142-5. PMID 15994560.
  4. ↑ Bhattacharyya, R.P., Remenyi, A., Good, M.C., Bashor, C.J., Falick, A.M. et al. (Feb 10 2006) "The Ste5 scaffold allosterically modulates signaling output of the yeast mating pathway". Science 311,(5762): 822-6. PMID 16424299.
  5. ↑ Liu, Y., Matthews, K.S. & Bondos, S.E. (Jul 24 2009) "Internal regulatory interactions determine DNA binding specificity by a Hox transcription factor". J Mol Biol 390,(4): 760-74. doi: S0022-2836(09)00629-9 [pii]
  6. ↑ Romero, P., Obradovic, Z., Kissinger, C.R., Villafranca, J.E., Garner, E. et al. 1998) "Thousands of proteins likely to have long disordered regions". Pac. Symp. Biocomputing. 3: 437-448. PMID 9697202.
  7. ↑ Wright, P.E. & Dyson, H.J. 1999) "Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm". J Mol Biol 293,(2): 321-31. PMID. 10550212
  8. 1 2 Galea, C.A., Nourse, A., Wang, Y., Sivakolundu, S.G., Heller, W.T. et al. (Feb 22 2008) "Role of intrinsic flexibility in signal transduction mediated by the cell cycle regulator, p27 Kip1". J Mol Biol 376,(3): 827-38. PMID 18177895.
  9. ↑ Fuxreiter, M., Tompa, P., Simon, I., Uversky, V.N., Hansen, J.C. et al. (Dec 2008) "Malleable machines take shape in eukaryotic transcriptional regulation". Nat Chem Biol 4,(12): 728-37. doi: nchembio.127 [pii] 10.1038/nchembio.127. PMID 19008886.
  10. ↑ Wang, Y., Fisher, J.C., Mathew, R., Ou, L., Otieno, S. et al. (April 2011) "Intrinsic disorder mediates the diverse regulatory functions of the Cdk inhibitor p21". Nat. Chem. Biol. 7: 214-221. PMID 21358637.
  11. ↑ Belch, Y., Yang, J., Liu, Y., Malkaram, S.A., Liu, R. et al. 2010) "Weakly positioned nucleosomes enhance the transcriptional competency of chromatin". PLoS ONE 5,(9): e12984. doi: 10.1371/journal.pone.0012984. PMID 20886052.
  12. ↑ Tsui, K., Dubuis, S., Gebbia, M., Morse, R.H., Barkai, N. et al. (Nov 2011) "Evolution of nucleosome occupancy: conservation of global properties and divergence of gene-specific patterns". Mol Cell Biol 31,(21): 4348-55. doi: MCB.05276-11 [pii] 10.1128/MCB.05276-11. PMID 21896781.
  13. ↑ Fuxreiter, M. (Jan 2012) "Fuzziness: linking regulation to protein dynamics". Mol Biosyst 8,(1): 168-77. doi: 10.1039/c1mb05234a. PMID 21927770.
  14. ↑ Nash, P., Tang, X., Orlicky, S., Chen, Q., Gertler, F.B. et al. (Nov 29 2001) "Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication". Nature 414,(6863): 514-21. doi. PMID 11734846.
  15. ↑ Mittag, T., Orlicky, S., Choy, W.Y., Tang, X., Lin, H. et al. (Nov 18 2008) "Dynamic equilibrium engagement of a polyvalent ligand with a single-site receptor". Proc Natl Acad Sci U S A 105,(46): 17772-7. doi: 0809222105 [pii] 10.1073/pnas.0809222105. PMID 19008353.
  16. ↑ Didry, D., Cantrelle, F.X., Husson, C., Roblin, P., Moorthy, A.M. et al. (Dec 23 2011) "How a single residue in individual beta-thymosin/WH2 domains controls their functions in actin assembly". EMBO J. doi: emboj2011461 [pii] 10.1038/emboj.2011.461. PMID 22193718.
  17. ↑ Fontes, M.R., Teh, T. & Kobe, B. (Apr 14 2000) "Structural basis of recognition of monopartite and bipartite nuclear localization sequences by mammalian importin-alpha". J Mol Biol 297,(5): 1183-94. PMID 10764582.
  18. ↑ Zor, T., Mayr, B.M., Dyson, H.J., Montminy, M.R. & Wright, P.E. (Nov 1 2002) "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 277,(44): 42241-8. PMID 12196545.
  19. ↑ Selenko, P., Gregorovic, G., Sprangers, R., Stier, G., Rhani, Z. et al. 2003) "Structural basis for the molecular recognition between human splicing factors U2AF65 and SF1/mBBP". Mol. Cell 11: 965-976. PMID 12718882.
  20. ↑ Pometun, M.S., Chekmenev, E.Y. & Wittebort, R.J. (Feb 27 2004) "Quantitative observation of backbone disorder in native elastin". J Biol Chem 279,(9): 7982-7. PMID 14625282.
  21. ↑ Sigalov, A., Aivazian, D. & Stern, L. (Feb 24 2004) "Homooligomerization of the cytoplasmic domain of the T cell receptor zeta chain and of other proteins containing the immunoreceptor tyrosine-based activation motif". Biochemistry 43,(7): 2049-61. PMID 14967045.
  22. ↑ Neduva, V. & Russell, R.B. (Jun 13 2005) "Linear motifs: evolutionary interaction switches". FEBS Lett 579,(15): 3342-5. PMID 15943979.
  23. ↑ Davey, N.E., Trave, G. & Gibson, T.J. (Mar 2011) "How viruses hijack cell regulation". Trends Biochem Sci 36,(3): 159-69. doi: S0968-0004(10)00200-8 [pii] 10.1016/j.tibs.2010.10.002. PMID 21146412.
  24. ↑ Lu, X., Hamkalo, B., Parseghian, M.H. & Hansen, J.C. (Jan 13 2009) "Chromatin condensing functions of the linker histone C-terminal domain are mediated by specific amino acid composition and intrinsic protein disorder". Biochemistry 48,(1): 164-72. doi: 10.1021/bi801636y 10.1021/bi801636y [pii]. PMID 19072710.
  25. ↑ McBryant, S.J., Klonoski, J., Sorensen, T.C., Norskog, S.S., Williams, S. et al. (Jun 19 2009) "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 284,(25): 16716-22. doi: M109.011288 [pii] 10.1074/jbc.M109.011288. PMID 19395382.
  26. ↑ Naud, J.F., McDuff, F.O., Sauve, S., Montagne, M., Webb, B.A. et al. (Sep 27 2005) "Structural and thermodynamical characterization of the complete p21 gene product of Max". Biochemistry 44,(38): 12746-58. doi: 10.1021/bi0500729. PMID 16171389.
  27. ↑ Lee, G.M., Pufall, M.A., Meeker, C.A., Kang, H.S., Graves, B.J. et al. (Oct 17 2008) "The affinity of Ets-1 for DNA is modulated by phosphorylation through transient interactions of an unstructured region". J Mol Biol 382,(4): 1014-30. doi. PMID 18692067.
  28. ↑ Fuxreiter, M., Simon, I. & Bondos, S. (Aug 2011) "Dynamic protein-DNA recognition: beyond what can be seen". Trends Biochem Sci 36,(8): 415-23. doi: S0968-0004(11)00059-4 [pii]10.1016/j.tibs.2011.04.006. PMID 21620710.
  29. ↑ Watson, M., Stott, K. & Thomas, J.O. (Dec 14 2007) "Mapping intramolecular interactions between domains in HMGB1 using a tail-truncation approach". J Mol Biol 374,(5): 1286-97. doi: S0022-2836(07)01287-9 [pii] 10.1016/j.jmb.2007.09.075. PMID 17988686.
  30. ↑ Olson, K.E., Narayanaswami, P., Vise, P.D., Lowry, D.F., Wold, M.S. et al. (Oct 2005) "Secondary structure and dynamics of an intrinsically unstructured linker domain". J Biomol Struct Dyn 23,(2): 113-24. doi: d=3021&c=4185&p=13080&do=detail [pii]. PMID 16060685.
  31. ↑ Ahmed, M.A., Bamm, V.V., Shi, L., Steiner-Mosonyi, M., Dawson, J.F. et al. (Jan 2009) "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 96,(1): 180-91. doi: S0006-3495(08)00040-4 [pii]10.1016/j.bpj.2008.10.003. PMID 19134474.
  32. ↑ Jonker, H.R., Wechselberger, R.W., Pinkse, M., Kaptein, R. & Folkers, G.E. (Apr 2006) "Gradual phosphorylation regulates PC4 coactivator function". FEBS J 273,(7): 1430-44. doi: EJB5165 [pii] 10.1111/j.1742-4658.2006.05165.x. PMID 16689930.
  33. ↑ Tsunaka, Y., Toga, J., Yamaguchi, H., Tate, S., Hirose, S. et al. (Sep 4 2009) "Phosphorylated intrinsically disordered region of FACT masks its nucleosomal DNA binding elements". J Biol Chem 284,(36): 24610-21. doi: M109.001958 [pii] 10.1074/jbc.M109.001958. PMID 19605348.
  34. ↑ Tanaka, T., Kawashima, H., Yeh, E.T. & Kamitani, T. (Aug 29 2003) "Regulation of the NEDD8 conjugation system by a splicing variant, NUB1L". J Biol Chem 278,(35): 32905-13. doi: 10.1074/jbc.M212057200 M212057200 [pii]. PMID 12816948.
  35. ↑ Liu, Y., Matthews, K.S. & Bondos, S.E. (Jul 25 2008) "Multiple intrinsically disordered sequences alter DNA binding by the homeodomain of the Drosophila hox protein ultrabithorax". J Biol Chem 283,(30): 20874-87. PMID 18508761.
  36. ↑ Brayer, K.J., Lynch, V.J. & Wagner, G.P. (Aug 9 2011) "Evolution of a derived protein-protein interaction between HoxA11 and Foxo1a in mammals caused by changes in intramolecular regulation". Proc Natl Acad Sci U S A 108,(32): E414-20. doi: 1100990108 [pii]10.1073/pnas.1100990108. PMID 21788518.
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