Nejasni kompleks

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NMR-na struktura inhibitora ciklin-zavisne kinaze Sic1 sa ubikvitin-ligazom Cdc4 (siva). Od devet fosforilacijskih mjesta Sic 1 (sfere) prikazani su kontakti sa T45 i S76 (narandžasti i plavi).
Nejasna veza (prikazana isprekidanom linijom) ultrabitoraksnog faktora transkripcija (narandžasta) povezuje homedomene i ekstradentikulni homedomen (plava) (PDB kôd 1bi). Alternativno spajanje modulira dužinu nejasnog područja, a time i afinitet vezanja njegove DNK (siva) Ostala regulatorna nejasna područja ultrabitoraksa također su prikazana tačkastim linijama

Nejasni kompleksi ili neizraziti kompleksi su proteinski kompleksi, gdje postoji strukturna dvosmislenost ili postojeća višestrukost i potrebni su za biološke funkcije.[1][2] Promjena, skraćivanje ili uklanjanje konformacijski dvosmislenih regija utiče na aktivnost odgovarajućih kompleksa.[3][4][5] Nejasne komplekse uglavnom formiraju [[suštinski nestrukturirani proteini| suštinski poremećeni proteini.[6][7] Strukturna multiplikacija obično leži u osnovi funkcijske višestrukosti proteinskih kompleksa[8][9][10] slijedeći nejasnu logiku. Izraziti načini vezanja nukleosoma također se smatraju posebnim nejasnim slučajem.[11][12]

Historijska pozadina[uredi | uredi izvor]

Gotovo 50 godina molekulska biologija temeljila se na dvije dogme: (1) izjednačavanju biološke funkcije proteina s jedinstvenom trodimenzijskom strukturom i (2) pretpostavljanju izuzetne specifičnosti u proteinskim kompleksima. Specifičnost/ elektivnost osigurava se nedvosmislenim skupom interakcija formiranih između proteina i njegovog liganda (drugog proteina, DNK, RNK ili male molekule). Mnogi proteinski kompleksi, međutim, sadrže funkcijski važne / kritične regije, koje ostaju vrlo dinamične u kompleksu ili usvajaju različite konformacije .[13] Ovaj fenomen definira se nejasnošću. Najvažniji primjer je ciklin-zavisni inhibitor kinaze Sic1, koji se veže za SCF podjedinicu Cdc4 u fosforilacijski ovisnom postupku.[14] Neregularne sekundarne strukture se postižu nakon fosforilacije, uz izmjenu različitih mjesta fosforilacije u kompleksu.[15]

Klasifikacija nejasnih kompleksa[uredi | uredi izvor]

Strukturna dvosmislenost u proteinskim kompleksima pokriva širok spektar.[1] U polimorfnom kompleksu, protein usvaja dvije ili više različitih konformacija, nakon vezanja za istog partnera i te se konformacije mogu riješiti.[16] Clamp,[17] flankiranjem (bočnom konfiguracijom) [18][19] i slučajnim kompleksima,[20][21] koji su dinamični, gdje se dvosmislene konformacije međusobno izmjenjuju i ne mogu se riješiti. Interakcije u nejasnim kompleksima obično posreduju kratki motivi.[22] Bočni regioni tolerantni su na promjene sekvence sve dok se održava aminokiselinska kompozicija, naprimjer u slučaju histonskih linker C-krajnjih domena [23] i H4 histona domena N-kraja.[24]

Regulacijski putevi preko nejasne regija[uredi | uredi izvor]

Nejasna područja moduliraju konformacijsku ravnotežu [25] ilu fleksibilnost [3][26] interfejsa vezanja, putem privremene interakcije.[27] Dynamic regions can also compete with binding sites[28] or tether them to the target.[29] Modifikacije nejasnih područja daljnjim interakcijama,[8][30] ili posttranslacijskim modifikacijama[31][32] utiču na afinitet vezanja ili specifičnost. Alternativna prerada mogu modulirati dužinu nejasnih regija, što rezultira vezanjem ovisno o kontekstu (npr. tkivno-specifičnos) na kompleksu.[33][34][35] EGF / MAPK, TGF-β i WNT/beskrilni signalni putevi koriste nejasna područja specifična za tkivo.

Reference[uredi | uredi izvor]

  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.|date=February 2018}}
  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.
  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.
  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.
  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.
  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.