Jump to content

Fuzzy complex

Edit links
From Wikipedia, the free encyclopedia
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 homeodomain with the Extradenticle homeodomain (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

[edit]

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

[edit]

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] 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 [23] and H4 histone N-terminal domains.[24]

Regulatory pathways via fuzzy regions

[edit]

Fuzzy regions modulate the conformational equilibrium [25] or flexibility [3][26] of the binding interface via transient interactions.[27] Dynamic regions can also compete with binding sites[28] or tether them to the target.[29] Modifications of fuzzy regions by further interactions,[8][30] or posttranslational modifications[31][32] 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.[33][34][35] EGF/MAPK, TGF-β and WNT/Wingless signaling pathways employ tissue-specific fuzzy regions.

References

[edit]
  1. ^ a b Tompa, Peter; Fuxreiter, Monika (2008). "Fuzzy complexes: Polymorphism and structural disorder in protein–protein interactions". Trends in Biochemical Sciences. 33 (1): 2–8. doi:10.1016/j.tibs.2007.10.003. PMID 18054235.
  2. ^ Fuxreiter, M. & Tompa, P. (2011) Fuzziness: Structural Disorder in Protein Complexes Austin, New York.[page needed]
  3. ^ a b Pufall, M. A; Lee, Gregory M; Nelson, Mary L; Kang, Hyun-Seo; Velyvis, Algirdas; Kay, Lewis E; McIntosh, Lawrence P; Graves, Barbara J (2005). "Variable Control of Ets-1 DNA Binding by Multiple Phosphates in an Unstructured Region". Science. 309 (5731): 142–5. Bibcode:2005Sci...309..142P. doi:10.1126/science.1111915. PMID 15994560.
  4. ^ Bhattacharyya, R. P; Reményi, Attila; Good, Matthew C; Bashor, Caleb J; Falick, Arnold M; Lim, Wendell A (2006). "The Ste5 Scaffold Allosterically Modulates Signaling Output of the Yeast Mating Pathway". Science. 311 (5762): 822–6. Bibcode:2006Sci...311..822B. doi:10.1126/science.1120941. PMID 16424299. S2CID 13882487.
  5. ^ Liu, Ying; Matthews, Kathleen S; Bondos, Sarah E (2009). "Internal Regulatory Interactions Determine DNA Binding Specificity by a Hox Transcription Factor". Journal of Molecular Biology. 390 (4): 760–74. doi:10.1016/j.jmb.2009.05.059. PMC 2739810. PMID 19481089.
  6. ^ Romero, P; Obradovic, Z; Kissinger, C. R; Villafranca, J. E; Garner, E; Guilliot, S; Dunker, A. K (1998). "Thousands of proteins likely to have long disordered regions". Pacific Symposium on Biocomputing: 437–48. PMID 9697202.
  7. ^ Wright, Peter E; Dyson, H. Jane (1999). "Intrinsically unstructured proteins: Re-assessing the protein structure-function paradigm". Journal of Molecular Biology. 293 (2): 321–31. doi:10.1006/jmbi.1999.3110. PMID 10550212.
  8. ^ a b Galea, Charles A; Nourse, Amanda; Wang, Yuefeng; Sivakolundu, Sivashankar G; Heller, William T; Kriwacki, Richard W (2008). "Role of Intrinsic Flexibility in Signal Transduction Mediated by the Cell Cycle Regulator, p27Kip1". Journal of Molecular Biology. 376 (3): 827–38. doi:10.1016/j.jmb.2007.12.016. PMC 2350195. PMID 18177895.
  9. ^ Fuxreiter, Monika; Tompa, Peter; Simon, István; Uversky, Vladimir N; Hansen, Jeffrey C; Asturias, Francisco J (2008). "Malleable machines take shape in eukaryotic transcriptional regulation". Nature Chemical Biology. 4 (12): 728–37. doi:10.1038/nchembio.127. PMC 2921704. PMID 19008886.
  10. ^ Wang, Yuefeng; Fisher, John C; Mathew, Rose; Ou, Li; Otieno, Steve; Sublet, Jack; Xiao, Limin; Chen, Jianhan; Roussel, Martine F; Kriwacki, Richard W (2011). "Intrinsic disorder mediates the diverse regulatory functions of the Cdk inhibitor p21". Nature Chemical Biology. 7 (4): 214–21. doi:10.1038/nchembio.536. PMC 3124363. PMID 21358637.
  11. ^ Belch, Yaakov; Yang, Jingyi; Liu, Yang; Malkaram, Sridhar A; Liu, Rong; Riethoven, Jean-Jack M; Ladunga, Istvan (2010). "Weakly Positioned Nucleosomes Enhance the Transcriptional Competency of Chromatin". PLOS ONE. 5 (9): e12984. Bibcode:2010PLoSO...512984B. doi:10.1371/journal.pone.0012984. PMC 2945322. PMID 20886052.
  12. ^ Tsui, K; Dubuis, S; Gebbia, M; Morse, R. H; Barkai, N; Tirosh, I; Nislow, C (2011). "Evolution of Nucleosome Occupancy: Conservation of Global Properties and Divergence of Gene-Specific Patterns". Molecular and Cellular Biology. 31 (21): 4348–55. doi:10.1128/MCB.05276-11. PMC 3209338. PMID 21896781.
  13. ^ Fuxreiter, Monika (2012). "Fuzziness: Linking regulation to protein dynamics". Molecular BioSystems. 8 (1): 168–77. doi:10.1039/c1mb05234a. PMID 21927770.
  14. ^ Nash, Piers; Tang, Xiaojing; Orlicky, Stephen; Chen, Qinghua; Gertler, Frank B; Mendenhall, Michael D; Sicheri, Frank; Pawson, Tony; Tyers, Mike (2001). "Multisite phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication". Nature. 414 (6863): 514–21. Bibcode:2001Natur.414..514N. doi:10.1038/35107009. PMID 11734846. S2CID 16924667.
  15. ^ Mittag, T; Orlicky, S; Choy, W.-Y; Tang, X; Lin, H; Sicheri, F; Kay, L. E; Tyers, M; Forman-Kay, J. D (2008). "Dynamic equilibrium engagement of a polyvalent ligand with a single-site receptor". Proceedings of the National Academy of Sciences. 105 (46): 17772–7. Bibcode:2008PNAS..10517772M. doi:10.1073/pnas.0809222105. JSTOR 25465359. PMC 2582940. PMID 19008353.
  16. ^ Didry, Dominique; Cantrelle, Francois-Xavier; Husson, Clotilde; Roblin, Pierre; Moorthy, Anna M Eswara; Perez, Javier; Le Clainche, Christophe; Hertzog, Maud; Guittet, Eric; Carlier, Marie-France; Van Heijenoort, Carine; Renault, Louis (2012). "How a single residue in individual β-thymosin/WH2 domains controls their functions in actin assembly". The EMBO Journal. 31 (4): 1000–13. doi:10.1038/emboj.2011.461. PMC 3280557. PMID 22193718.
  17. ^ Fontes, Marcos R.M; Teh, Trazel; Kobe, Bostjan (2000). "Structural basis of recognition of monopartite and bipartite nuclear localization sequences by mammalian importin-α". Journal of Molecular Biology. 297 (5): 1183–94. doi:10.1006/jmbi.2000.3642. PMID 10764582.
  18. ^ Zor, Tsaffrir; Mayr, Bernhard M; Dyson, H. Jane; Montminy, Marc R; Wright, Peter E (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". Journal of Biological Chemistry. 277 (44): 42241–8. doi:10.1074/jbc.M207361200. PMID 12196545.
  19. ^ Selenko, Philipp; Gregorovic, Goran; Sprangers, Remco; Stier, Gunter; Rhani, Zakaria; Krämer, Angela; Sattler, Michael (2003). "Structural Basis for the Molecular Recognition between Human Splicing Factors U2AF65 and SF1/mBBP". Molecular Cell. 11 (4): 965–76. doi:10.1016/S1097-2765(03)00115-1. PMID 12718882.
  20. ^ Pometun, Maxim S; Chekmenev, Eduard Y; Wittebort, Richard J (2004). "Quantitative Observation of Backbone Disorder in Native Elastin". Journal of Biological Chemistry. 279 (9): 7982–7. doi:10.1074/jbc.M310948200. PMID 14625282.
  21. ^ Sigalov, Alexander; Aivazian, Dikran; Stern, Lawrence (2004). "Homooligomerization of the Cytoplasmic Domain of the T Cell Receptor ζ Chain and of Other Proteins Containing the Immunoreceptor Tyrosine-Based Activation Motif". Biochemistry. 43 (7): 2049–61. doi:10.1021/bi035900h. PMID 14967045.
  22. ^ Davey, Norman E; Travé, Gilles; Gibson, Toby J (2011). "How viruses hijack cell regulation". Trends in Biochemical Sciences. 36 (3): 159–69. doi:10.1016/j.tibs.2010.10.002. PMID 21146412.
  23. ^ Lu, Xu; Hamkalo, Barbara; Parseghian, Missag H; Hansen, Jeffrey C (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. PMC 2644900. PMID 19072710.
  24. ^ McBryant, Steven J; Klonoski, Joshua; Sorensen, Troy C; Norskog, Sarah S; Williams, Sere; Resch, Michael G; Toombs, James A; Hobdey, Sarah E; Hansen, Jeffrey C (2009). "Determinants of Histone H4 N-terminal Domain Function during Nucleosomal Array Oligomerization". Journal of Biological Chemistry. 284 (25): 16716–22. doi:10.1074/jbc.M109.011288. PMC 2719306. PMID 19395382.
  25. ^ Naud, Jean-François; McDuff, François-Olivier; Sauvé, Simon; Montagne, Martin; Webb, Bradley A; Smith, Steven P; Chabot, Benoit; Lavigne, Pierre (2005). "Structural and Thermodynamical Characterization of the Complete p21 Gene Product of Max". Biochemistry. 44 (38): 12746–58. doi:10.1021/bi0500729. PMID 16171389.
  26. ^ Lee, Gregory M; Pufall, Miles A; Meeker, Charles A; Kang, Hyun-Seo; Graves, Barbara J; McIntosh, Lawrence P (2008). "The Affinity of Ets-1 for DNA is Modulated by Phosphorylation Through Transient Interactions of an Unstructured Region". Journal of Molecular Biology. 382 (4): 1014–30. doi:10.1016/j.jmb.2008.07.064. PMC 4808631. PMID 18692067.
  27. ^ Fuxreiter, Monika; Simon, Istvan; Bondos, Sarah (2011). "Dynamic protein–DNA recognition: Beyond what can be seen". Trends in Biochemical Sciences. 36 (8): 415–23. doi:10.1016/j.tibs.2011.04.006. PMID 21620710.
  28. ^ Watson, Matthew; Stott, Katherine; Thomas, Jean O (2007). "Mapping Intramolecular Interactions between Domains in HMGB1 using a Tail-truncation Approach". Journal of Molecular Biology. 374 (5): 1286–97. doi:10.1016/j.jmb.2007.09.075. PMID 17988686.
  29. ^ Olson, Katie E; Narayanaswami, Pranesh; Vise, Pamela D; Lowry, David F; Wold, Marc S; Daughdrill, Gary W (2005). "Secondary Structure and Dynamics of an Intrinsically Unstructured Linker Domain". Journal of Biomolecular Structure and Dynamics. 23 (2): 113–24. doi:10.1080/07391102.2005.10507052. PMID 16060685. S2CID 37429006.
  30. ^ Ahmed, Mumdooh A.M; Bamm, Vladimir V; Shi, Lichi; Steiner-Mosonyi, Marta; Dawson, John F; Brown, Leonid; Harauz, George; Ladizhansky, Vladimir (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". Biophysical Journal. 96 (1): 180–91. Bibcode:2009BpJ....96..180A. doi:10.1016/j.bpj.2008.10.003. PMC 2710047. PMID 19134474.
  31. ^ Jonker, Hendrik R. A; Wechselberger, Rainer W; Pinkse, Martijn; Kaptein, Robert; Folkers, Gert E (2006). "Gradual phosphorylation regulates PC4 coactivator function". FEBS Journal. 273 (7): 1430–44. doi:10.1111/j.1742-4658.2006.05165.x. hdl:1874/19762. PMID 16689930. S2CID 38856641.
  32. ^ Tsunaka, Yasuo; Toga, Junko; Yamaguchi, Hiroto; Tate, Shin-Ichi; Hirose, Susumu; Morikawa, Kosuke (2009). "Phosphorylated Intrinsically Disordered Region of FACT Masks Its Nucleosomal DNA Binding Elements". Journal of Biological Chemistry. 284 (36): 24610–21. doi:10.1074/jbc.M109.001958. PMC 2782050. PMID 19605348.
  33. ^ Tanaka, Tomoaki; Kawashima, Hidenori; Yeh, Edward T. H; Kamitani, Tetsu (2003). "Regulation of the NEDD8 Conjugation System by a Splicing Variant, NUB1L". Journal of Biological Chemistry. 278 (35): 32905–13. doi:10.1074/jbc.M212057200. PMID 12816948.
  34. ^ Liu, Ying; Matthews, Kathleen S; Bondos, Sarah E (2008). "Multiple Intrinsically Disordered Sequences Alter DNA Binding by the Homeodomain of the Drosophila Hox Protein Ultrabithorax". Journal of Biological Chemistry. 283 (30): 20874–87. doi:10.1074/jbc.M800375200. PMC 2475714. PMID 18508761.
  35. ^ Brayer, K. J; Lynch, V. J; Wagner, G. P (2011). "Evolution of a derived protein-protein interaction between HoxA11 and Foxo1a in mammals caused by changes in intramolecular regulation". Proceedings of the National Academy of Sciences. 108 (32): E414–20. Bibcode:2011PNAS..108E.414B. doi:10.1073/pnas.1100990108. PMC 3156161. PMID 21788518.
Retrieved from "https://wiki.riteme.site/w/index.php?title=Fuzzy_complex&oldid=1246589818"