Generic placeholder image

Current Protein & Peptide Science


ISSN (Print): 1389-2037
ISSN (Online): 1875-5550

Research Article

On the Potential Significance of the Intrinsically Disordered Regions in the Clostridiodes difficile Toxins A and B

Author(s): Nashwa El Hadidy, Vladimir N. Uversky* and Xingmin Sun*

Volume 23, Issue 3, 2022

Published on: 09 June, 2022

Page: [192 - 209] Pages: 18

DOI: 10.2174/1389203723666220518111801

Price: $65


Background: Clostridiodes (or Clostridium) difficile is a spore-forming, Gram-positive anaerobic bacterium that may cause symptoms ranging from diarrhea to pseudomembranous colitis. During the C. difficile infection (CDI), the two primary bacterial toxins, toxin A (TcdA) or toxin B (TcdB), disrupt host cell function mainly through the inactivation of small GTPases that regulate the actin cytoskeleton. Both toxins have complex structural organization containing several functional domains.

Methods: Analytical bioinformatics tools are used to compare the extent of disorder within TcdA and TcdB proteins, and to see if the existence of structural disorder can be used to explain the difference in the functionality of these toxins.

Results: This paper’s aim is to offer an overall review of the structural and functional differences between TcdA and TcdB.

Conclusion: Results of our multifactorial bioinformatics analysis revealed that intrinsic disorder may play a role in the multifunctionality of C. difficile major toxins TcdA and TcdB, suggesting that intrinsic disorder may be related to their pathogenic mechanisms.

Keywords: Bacterial toxin, binding promiscuity, intrinsic disorder, multifunctionality, protein-protein interactions, TcdA, TcdB.

« Previous
Graphical Abstract
Anderson, D.M.; Sheedlo, M.J.; Jensen, J.L.; Lacy, D.B. Structural insights into the transition of Clostridioides difficile binary toxin from prepore to pore. Nat. Microbiol., 2020, 5(1), 102-107.
[] [PMID: 31712627]
Kuehne, S.A.; Cartman, S.T.; Heap, J.T.; Kelly, M.L.; Cockayne, A.; Minton, N.P. The role of toxin A and toxin B in Clostridioides difficile infection. Nature, 2010, 467(7316), 711-713.
[] [PMID: 20844489]
Lyras, D.; O’Connor, J.R.; Howarth, P.M.; Sambol, S.P.; Carter, G.P.; Phumoonna, T.; Poon, R.; Adams, V.; Vedantam, G.; Johnson, S.; Gerding, D.N.; Rood, J.I. Toxin B is essential for virulence of Clostridioides difficile. Nature, 2009, 458(7242), 1176-1179.
[] [PMID: 19252482]
Pruitt, R.N.; Lacy, D.B. Toward a structural understanding of Clostridioides difficile toxins A and B. Front. Cell. Infect. Microbiol., 2012, 2, 28.
[] [PMID: 22919620]
Zhu, D.; Bullock, J.; He, Y.; Sun, X. Cwp22, a novel peptidoglycan cross-linking enzyme, plays pleiotropic roles in Clostridioides difficile. Environ. Microbiol., 2019, 21(8), 3076-3090.
[] [PMID: 31173438]
Riegler, M.; Sedivy, R.; Pothoulakis, C.; Hamilton, G.; Zacherl, J.; Bischof, G.; Cosentini, E.; Feil, W.; Schiessel, R.; LaMont, J.T. Clostrid-ioides difficile toxin B is more potent than toxin A in damaging human colonic epithelium in vitro. J. Clin. Invest., 1995, 95(5), 2004-2011.
[] [PMID: 7738167]
El Hadidy, N.; Uversky, V.N. Intrinsic disorder of the BAF complex: Roles in chromatin remodeling and disease development. Int. J. Mol. Sci., 2019, 20(21), E5260.
[] [PMID: 31652801]
Wright, P.E.; Dyson, H.J. Intrinsically unstructured proteins: Re-assessing the protein structure-function paradigm. J. Mol. Biol., 1999, 293(2), 321-331.
[] [PMID: 10550212]
Uversky, V.N.; Gillespie, J.R.; Fink, A.L. Why are “natively unfolded” proteins unstructured under physiologic conditions? Proteins, 2000, 41(3), 415-427.
[<415:AID-PROT130>3.0.CO;2-7] [PMID: 11025552]
Dunker, A.K.; Lawson, J.D.; Brown, C.J.; Williams, R.M.; Romero, P.; Oh, J.S.; Oldfield, C.J.; Campen, A.M.; Ratliff, C.M.; Hipps, K.W.; Ausio, J.; Nissen, M.S.; Reeves, R.; Kang, C.; Kissinger, C.R.; Bailey, R.W.; Griswold, M.D.; Chiu, W.; Garner, E.C.; Obradovic, Z. Intrin-sically disordered protein. J. Mol. Graph. Model., 2001, 19(1), 26-59.
[] [PMID: 11381529]
Dunker, A.K.; Obradovic, Z.; Romero, P.; Garner, E.C.; Brown, C.J. Intrinsic protein disorder in complete genomes. Genome Inform. Ser. Workshop Genome Inform., 2000, 11, 161-171.
[PMID: 11700597]
Ward, J.J.; Sodhi, J.S.; McGuffin, L.J.; Buxton, B.F.; Jones, D.T. Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J. Mol. Biol., 2004, 337(3), 635-645.
[] [PMID: 15019783]
Xue, B.; Dunker, A.K.; Uversky, V.N. Orderly order in protein intrinsic disorder distribution: Disorder in 3500 proteomes from viruses and the three domains of life. J. Biomol. Struct. Dyn., 2012, 30(2), 137-149.
[] [PMID: 22702725]
Peng, Z.; Yan, J.; Fan, X.; Mizianty, M.J.; Xue, B.; Wang, K.; Hu, G.; Uversky, V.N.; Kurgan, L. Exceptionally abundant exceptions: Com-prehensive characterization of intrinsic disorder in all domains of life. Cell. Mol. Life Sci., 2015, 72(1), 137-151.
[] [PMID: 24939692]
Jank, T.; Aktories, K. Structure and mode of action of clostridial glucosylating toxins: The ABCD model. Trends Microbiol., 2008, 16(5), 222-229.
[] [PMID: 18394902]
Genth, H.; Junemann, J.; Lämmerhirt, C.M.; Lücke, A.C.; Schelle, I.; Just, I.; Gerhard, R.; Pich, A. Difference in Mono-O-Glucosylation of Ras Subtype GTPases between toxin A and Toxin B From Clostridioides difficile strain 10463 and lethal toxin from Clostridium sordellii strain 6018. Front. Microbiol., 2018, 9, 3078.
[] [PMID: 30622517]
Genth, H.; Pauillac, S.; Schelle, I.; Bouvet, P.; Bouchier, C.; Varela-Chavez, C.; Just, I.; Popoff, M.R. Haemorrhagic toxin and lethal toxin from Clostridium sordellii strain vpi9048: Molecular characterization and comparative analysis of substrate specificity of the large clostrid-ial glucosylating toxins. Cell. Microbiol., 2014, 16(11), 1706-1721.
[] [PMID: 24905543]
D’Urzo, N.; Malito, E.; Biancucci, M.; Bottomley, M.J.; Maione, D.; Scarselli, M.; Martinelli, M. The structure of Clostridioides difficile toxin A glucosyltransferase domain bound to Mn2+ and UDP provides insights into glucosyltransferase activity and product release. FEBS J., 2012, 279(17), 3085-3097.
[] [PMID: 22747490]
Pruitt, R.N.; Chumbler, N.M.; Rutherford, S.A.; Farrow, M.A.; Friedman, D.B.; Spiller, B.; Lacy, D.B. Structural determinants of Clostridi-oides difficile toxin A glucosyltransferase activity. J. Biol. Chem., 2012, 287(11), 8013-8020.
[] [PMID: 22267739]
Just, I.; Wilm, M.; Selzer, J.; Rex, G.; von Eichel-Streiber, C.; Mann, M.; Aktories, K. The enterotoxin from Clostridioides difficile (ToxA) monoglucosylates the Rho proteins. J. Biol. Chem., 1995, 270(23), 13932-13936.
[] [PMID: 7775453]
von Eichel-Streiber, C.; Sauerborn, M.; Kuramitsu, H.K. Evidence for a modular structure of the homologous repetitive C-terminal carbo-hydrate-binding sites of Clostridioides difficile toxins and Streptococcus mutans glucosyltransferases. J. Bacteriol., 1992, 174(20), 6707-6710.
[] [PMID: 1307487]
Egerer, M.; Giesemann, T.; Jank, T.; Satchell, K.J.; Aktories, K. Auto-catalytic cleavage of Clostridioides difficile toxins A and B depends on cysteine protease activity. J. Biol. Chem., 2007, 282(35), 25314-25321.
[] [PMID: 17591770]
Genisyuerek, S.; Papatheodorou, P.; Guttenberg, G.; Schubert, R.; Benz, R.; Aktories, K. Structural determinants for membrane insertion, pore formation and translocation of Clostridioides difficile toxin B. Mol. Microbiol., 2011, 79(6), 1643-1654.
[] [PMID: 21231971]
Yuan, P.; Zhang, H.; Cai, C.; Zhu, S.; Zhou, Y.; Yang, X.; He, R.; Li, C.; Guo, S.; Li, S.; Huang, T.; Perez-Cordon, G.; Feng, H.; Wei, W. Chondroitin sulfate proteoglycan 4 functions as the cellular receptor for Clostridioides difficile toxin B. Cell Res., 2015, 25(2), 157-168.
[] [PMID: 25547119]
Olling, A.; Goy, S.; Hoffmann, F.; Tatge, H.; Just, I.; Gerhard, R. The repetitive oligopeptide sequences modulate cytopathic potency but are not crucial for cellular uptake of Clostridioides difficile toxin A. PLoS One, 2011, 6(3), e17623.
[] [PMID: 21445253]
Odumosu, O.; Nicholas, D.; Yano, H.; Langridge, W. AB toxins: A paradigm switch from deadly to desirable. Toxins (Basel), 2010, 2(7), 1612-1645.
[] [PMID: 22069653]
Chandrasekaran, R.; Lacy, D.B. The role of toxins in Clostridioides difficile infection. FEMS Microbiol. Rev., 2017, 41(6), 723-750.
[] [PMID: 29048477]
Chumbler, N.M.; Rutherford, S.A.; Zhang, Z.; Farrow, M.A.; Lisher, J.P.; Farquhar, E.; Giedroc, D.P.; Spiller, B.W.; Melnyk, R.A.; Lacy, D.B. Crystal structure of Clostridioides difficile toxin A. Nat. Microbiol., 2016, 1(1), 15002.
Uversky, V.N. Recent developments in the field of intrinsically disordered proteins: Intrinsic disorder-based emergence in cellular biology in light of the physiological and pathological liquid-liquid phase transitions. Annu. Rev. Biophys., 2021, 50(1), 135-156.
[] [PMID: 33503380]
Uversky, V.N. Unusual biophysics of intrinsically disordered proteins. Biochim. Biophys. Acta, 2013, 1834(5), 932-951.
[] [PMID: 23269364]
Uversky, V.N. Intrinsic disorder-based protein interactions and their modulators. Curr. Pharm. Des., 2013, 19(23), 4191-4213.
[] [PMID: 23170892]
Uversky, V.N. Functional roles of transiently and intrinsically disordered regions within proteins. FEBS J., 2015, 282(7), 1182-1189.
[] [PMID: 25631540]
Uversky, V.N. p53 Proteoforms and intrinsic disorder: An illustration of the protein structure-function continuum concept. Int. J. Mol. Sci., 2016, 17(11), 1874.
[] [PMID: 27834926]
Habchi, J.; Tompa, P.; Longhi, S.; Uversky, V.N. Introducing protein intrinsic disorder. Chem. Rev., 2014, 114(13), 6561-6588.
[] [PMID: 24739139]
van der Lee, R.; Buljan, M.; Lang, B.; Weatheritt, R.J.; Daughdrill, G.W.; Dunker, A.K.; Fuxreiter, M.; Gough, J.; Gsponer, J.; Jones, D.T.; Kim, P.M.; Kriwacki, R.W.; Oldfield, C.J.; Pappu, R.V.; Tompa, P.; Uversky, V.N.; Wright, P.E.; Babu, M.M. Classification of intrinsically disordered regions and proteins. Chem. Rev., 2014, 114(13), 6589-6631.
[] [PMID: 24773235]
Dunker, A.K.; Brown, C.J.; Obradovic, Z. Identification and functions of usefully disordered proteins. Adv. Protein Chem., 2002, 62, 25-49.
[] [PMID: 12418100]
Dunker, A.K.; Brown, C.J.; Lawson, J.D.; Iakoucheva, L.M. Obradović Z. Intrinsic disorder and protein function. Biochemistry, 2002, 41(21), 6573-6582.
[] [PMID: 12022860]
Uversky, V.N. A decade and a half of protein intrinsic disorder: Biology still waits for physics. Protein Sci., 2013, 22(6), 693-724.
[] [PMID: 23553817]
Tompa, P.; Csermely, P. The role of structural disorder in the function of RNA and protein chaperones. FASEB J., 2004, 18(11), 1169-1175.
[] [PMID: 15284216]
Iakoucheva, L.M.; Radivojac, P.; Brown, C.J.; O’Connor, T.R.; Sikes, J.G.; Obradovic, Z.; Dunker, A.K. The importance of intrinsic dis-order for protein phosphorylation. Nucleic Acids Res., 2004, 32(3), 1037-1049.
[] [PMID: 14960716]
Pejaver, V.; Hsu, W.L.; Xin, F.; Dunker, A.K.; Uversky, V.N.; Radivojac, P. The structural and functional signatures of proteins that un-dergo multiple events of post-translational modification. Protein Sci., 2014, 23(8), 1077-1093.
[] [PMID: 24888500]
Uversky, V.N. Multitude of binding modes attainable by intrinsically disordered proteins: A portrait gallery of disorder-based complexes. Chem. Soc. Rev., 2011, 40(3), 1623-1634.
[] [PMID: 21049125]
Tompa, P.; Fuxreiter, M. Fuzzy complexes: Polymorphism and structural disorder in protein-protein interactions. Trends Biochem. Sci., 2008, 33(1), 2-8.
[] [PMID: 18054235]
Fuxreiter, M. Towards a stochastic paradigm: From fuzzy ensembles to cellular functions. Molecules, 2018, 23(11), 3008.
[] [PMID: 30453632]
Miskei, M.; Gregus, A.; Sharma, R.; Duro, N.; Zsolyomi, F.; Fuxreiter, M. Fuzziness enables context dependence of protein interactions. FEBS Lett., 2017, 591(17), 2682-2695.
[] [PMID: 28762260]
Gruet, A.; Dosnon, M.; Blocquel, D.; Brunel, J.; Gerlier, D.; Das, R.K.; Bonetti, D.; Gianni, S.; Fuxreiter, M.; Longhi, S.; Bignon, C. Fuzzy regions in an intrinsically disordered protein impair protein-protein interactions. FEBS J., 2016, 283(4), 576-594.
[] [PMID: 26684000]
Sharma, R.; Raduly, Z.; Miskei, M.; Fuxreiter, M. Fuzzy complexes: Specific binding without complete folding. FEBS Lett., 2015, 589 (19PartA)(19 Pt A), 2533-2542.
[] [PMID: 26226339]
Fuxreiter, M.; Tompa, P. Fuzzy complexes: A more stochastic view of protein function. Adv. Exp. Med. Biol., 2012, 725, 1-14.
[] [PMID: 22399315]
Fuxreiter, M. Fuzziness: Linking regulation to protein dynamics. Mol. Biosyst., 2012, 8(1), 168-177.
[] [PMID: 21927770]
Oldfield, C.J.; Meng, J.; Yang, J.Y.; Yang, M.Q.; Uversky, V.N.; Dunker, A.K. Flexible nets: Disorder and induced fit in the associations of p53 and 14-3-3 with their partners. BMC Genomics, 2008, 9(S1)(Suppl. 1), S1.
[] [PMID: 18366598]
Alterovitz, W.L.; Faraggi, E.; Oldfield, C.J.; Meng, J.; Xue, B.; Huang, F.; Romero, P.; Kloczkowski, A.; Uversky, V.N.; Dunker, A.K. Many-to-one binding by intrinsically disordered protein regions. Pac. Symp. Biocomput., 2020, 25, 159-170.
[PMID: 31797594]
Borgia, A.; Borgia, M.B.; Bugge, K.; Kissling, V.M.; Heidarsson, P.O.; Fernandes, C.B.; Sottini, A.; Soranno, A.; Buholzer, K.J.; Nettels, D.; Kragelund, B.B.; Best, R.B.; Schuler, B. Extreme disorder in an ultrahigh-affinity protein complex. Nature, 2018, 555(7694), 61-66.
[] [PMID: 29466338]
Uversky, V.N. Intrinsically disordered proteins in overcrowded milieu: Membrane-less organelles, phase separation, and intrinsic disor-der. Curr. Opin. Struct. Biol., 2017, 44, 18-30.
[] [PMID: 27838525]
Uversky, V.N. Protein intrinsic disorder-based liquid-liquid phase transitions in biological systems: Complex coacervates and membrane-less organelles. Adv. Colloid Interface Sci., 2017, 239, 97-114.
[] [PMID: 27291647]
UniProt Consortium. T. UniProt: The universal protein knowledgebase. Nucleic Acids Res., 2018, 46(5), 2699.
[] [PMID: 29425356]
Apweiler, R.; Bairoch, A.; Wu, C.H.; Barker, W.C.; Boeckmann, B.; Ferro, S.; Gasteiger, E.; Huang, H.; Lopez, R.; Magrane, M.; Martin, M.J.; Natale, D.A.; O’Donovan, C.; Redaschi, N.; Yeh, L.S. UniProt: The universal protein knowledgebase. Nucleic Acids Res., 2004, 32(Database issue), D115-D119.
[] [PMID: 14681372]
Mészáros, B.; Erdos, G.; Dosztányi, Z. IUPred2A: Context-dependent prediction of protein disorder as a function of redox state and pro-tein binding. Nucleic Acids Res., 2018, 46(W1), W329-W337.
[] [PMID: 29860432]
Erdős, G.; Dosztányi, Z. Analyzing protein disorder with IUPred2A. Curr. Protoc. Bioinformatics, 2020, 70(1), e99.
[] [PMID: 32237272]
Dosztányi, Z.; Mészáros, B.; Simon, I. ANCHOR: Web server for predicting protein binding regions in disordered proteins. Bioinformatics, 2009, 25(20), 2745-2746.
[] [PMID: 19717576]
Oates, M.E.; Romero, P.; Ishida, T.; Ghalwash, M.; Mizianty, M.J.; Xue, B.; Dosztányi, Z.; Uversky, V.N.; Obradovic, Z.; Kurgan, L.; Dunker, A.K.; Gough, J. D2P2: Database of disordered protein predictions. Nucleic Acids Res., 2013, 41(Database issue), D508-D516.
[PMID: 23203878]
Szklarczyk, D.; Franceschini, A.; Kuhn, M.; Simonovic, M.; Roth, A.; Minguez, P.; Doerks, T.; Stark, M.; Muller, J.; Bork, P.; Jensen, L.J.; von Mering, C. The STRING database in 2011: Functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res., 2011, 39(Database issue), D561-D568.
[] [PMID: 21045058]
Peng, K.; Radivojac, P.; Vucetic, S.; Dunker, A.K.; Obradovic, Z. Length-dependent prediction of protein intrinsic disorder. BMC Bioinformatics, 2006, 7(1), 208.
[] [PMID: 16618368]
Romero, P.; Obradovic, Z.; Li, X.; Garner, E.C.; Brown, C.J.; Dunker, A.K. Sequence complexity of disordered protein. Proteins, 2001, 42(1), 38-48.
[<38:AID-PROT50>3.0.CO;2-3] [PMID: 11093259]
Xue, B.; Dunbrack, R.L.; Williams, R.W.; Dunker, A.K.; Uversky, V.N. PONDR-FIT: A meta-predictor of intrinsically disordered amino acids. Biochim. Biophys. Acta, 2010, 1804(4), 996-1010.
[] [PMID: 20100603]
Peng, K.; Vucetic, S.; Radivojac, P.; Brown, C.J.; Dunker, A.K.; Obradovic, Z. Optimizing long intrinsic disorder predictors with protein evolutionary information. J. Bioinform. Comput. Biol., 2005, 3(1), 35-60.
[] [PMID: 15751111]
Dosztányi, Z.; Csizmok, V.; Tompa, P.; Simon, I. IUPred: Web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content. Bioinformatics, 2005, 21(16), 3433-3434.
[] [PMID: 15955779]
Dosztányi, Z.; Csizmók, V.; Tompa, P.; Simon, I. The pairwise energy content estimated from amino acid composition discriminates be-tween folded and intrinsically unstructured proteins. J. Mol. Biol., 2005, 347(4), 827-839.
[] [PMID: 15769473]
Rajagopalan, K.; Mooney, S.M.; Parekh, N.; Getzenberg, R.H.; Kulkarni, P. A majority of the cancer/testis antigens are intrinsically disor-dered proteins. J. Cell. Biochem., 2011, 112(11), 3256-3267.
[] [PMID: 21748782]
Oldfield, C.J.; Dunker, A.K. Intrinsically disordered proteins and intrinsically disordered protein regions. Annu. Rev. Biochem., 2014, 83(1), 553-584.
[] [PMID: 24606139]
Uversky, V.N.; Dunker, A.K. Understanding protein non-folding. Biochim. Biophys. Acta, 2010, 1804(6), 1231-1264.
[] [PMID: 20117254]
Uversky, V.N. The multifaceted roles of intrinsic disorder in protein complexes. FEBS Lett., 2015, 589(19 Pt A), 2498-2506.
[] [PMID: 26073257]
Mammen, M.; Choi, S.K.; Whitesides, G.M. Polyvalent interactions in biological systems: Implications for design and use of multivalent ligands and inhibitors. Angew. Chem. Int. Ed. Engl., 1998, 37(20), 2754-2794.
[<2754:AID-ANIE2754>3.0.CO;2-3] [PMID: 29711117]
Schulz, G.E. Nucleotide Binding Proteins. In: Molecular Mechanism of Biological Recognition; Balaban, M., Ed.; Elsevier/North- Holland Biomedical Press: New York, 1979; pp. 79-94.
Wright, P.E.; Dyson, H.J. Linking folding and binding. Curr. Opin. Struct. Biol., 2009, 19(1), 31-38.
[] [PMID: 19157855]
Meador, W.E.; Means, A.R.; Quiocho, F.A. Modulation of calmodulin plasticity in molecular recognition on the basis of x-ray structures. Science, 1993, 262(5140), 1718-1721.
[] [PMID: 8259515]
Kriwacki, R.W.; Hengst, L.; Tennant, L.; Reed, S.I.; Wright, P.E. Structural studies of p21Waf1/Cip1/Sdi1 in the free and Cdk2-bound state: Conformational disorder mediates binding diversity. Proc. Natl. Acad. Sci. USA, 1996, 93(21), 11504-11509.
[] [PMID: 8876165]
Dunker, A.K.; Garner, E.; Guilliot, S.; Romero, P.; Albrecht, K.; Hart, J.; Obradovic, Z.; Kissinger, C.; Villafranca, J.E. Protein disorder and the evolution of molecular recognition: Theory, predictions and observations. Pac. Symp. Biocomput., 1998, 473-484.
[PMID: 9697205]
Uversky, V.N. Protein folding revisited. A polypeptide chain at the folding-misfolding-nonfolding cross-roads: Which way to go? Cell. Mol. Life Sci., 2003, 60(9), 1852-1871.
[] [PMID: 14523548]
Dunker, A.K.; Cortese, M.S.; Romero, P.; Iakoucheva, L.M.; Uversky, V.N. Flexible nets. The roles of intrinsic disorder in protein inter-action networks. FEBS J., 2005, 272(20), 5129-5148.
[] [PMID: 16218947]
Dajani, R.; Fraser, E.; Roe, S.M.; Yeo, M.; Good, V.M.; Thompson, V.; Dale, T.C.; Pearl, L.H. Structural basis for recruitment of glycogen synthase kinase 3beta to the axin-APC scaffold complex. EMBO J., 2003, 22(3), 494-501.
[] [PMID: 12554650]
Dyson, H.J.; Wright, P.E. Coupling of folding and binding for unstructured proteins. Curr. Opin. Struct. Biol., 2002, 12(1), 54-60.
[] [PMID: 11839490]
Hsu, W.L.; Oldfield, C.J.; Xue, B.; Meng, J.; Huang, F.; Romero, P.; Uversky, V.N.; Dunker, A.K. Exploring the binding diversity of in-trinsically disordered proteins involved in one-to-many binding. Protein Sci., 2013, 22(3), 258-273.
[] [PMID: 23233352]
Hazy, E.; Tompa, P. Limitations of induced folding in molecular recognition by intrinsically disordered proteins. ChemPhysChem, 2009, 10(9-10), 1415-1419.
[] [PMID: 19462392]
Sigalov, A.; Aivazian, D.; Stern, L. Homooligomerization of the cytoplasmic domain of the T cell receptor zeta chain and of other proteins containing the immunoreceptor tyrosine-based activation motif. Biochemistry, 2004, 43(7), 2049-2061.
[] [PMID: 14967045]
Sigalov, A.B.; Zhuravleva, A.V.; Orekhov, V.Y. Binding of intrinsically disordered proteins is not necessarily accompanied by a structural transition to a folded form. Biochimie, 2007, 89(3), 419-421.
[] [PMID: 17174464]
Permyakov, S.E.; Millett, I.S.; Doniach, S.; Permyakov, E.A.; Uversky, V.N. Natively unfolded C-terminal domain of caldesmon remains substantially unstructured after the effective binding to calmodulin. Proteins, 2003, 53(4), 855-862. Na.
[] [PMID: 14635127]
Patil, A.; Nakamura, H. Disordered domains and high surface charge confer hubs with the ability to interact with multiple proteins in inter-action networks. FEBS Lett., 2006, 580(8), 2041-2045.
[] [PMID: 16542654]
Ekman, D.; Light, S.; Björklund, A.K.; Elofsson, A. What properties characterize the hub proteins of the protein-protein interaction net-work of Saccharomyces cerevisiae? Genome Biol., 2006, 7(6), R45.
[] [PMID: 16780599]
Haynes, C.; Oldfield, C.J.; Ji, F.; Klitgord, N.; Cusick, M.E.; Radivojac, P.; Uversky, V.N.; Vidal, M.; Iakoucheva, L.M. Intrinsic disorder is a common feature of hub proteins from four eukaryotic interactomes. PLOS Comput. Biol., 2006, 2(8), e100.
[] [PMID: 16884331]
Dosztányi, Z.; Chen, J.; Dunker, A.K.; Simon, I.; Tompa, P. Disorder and sequence repeats in hub proteins and their implications for net-work evolution. J. Proteome Res., 2006, 5(11), 2985-2995.
[] [PMID: 17081050]
Singh, G.P.; Dash, D. Intrinsic disorder in yeast transcriptional regulatory network. Proteins, 2007, 68(3), 602-605.
[] [PMID: 17510967]
Singh, G.P.; Ganapathi, M.; Dash, D. Role of intrinsic disorder in transient interactions of hub proteins. Proteins, 2007, 66(4), 761-765.
[] [PMID: 17154416]
Pruitt, R.N.; Chambers, M.G.; Ng, K.K.; Ohi, M.D.; Lacy, D.B. Structural organization of the functional domains of Clostridioides difficile toxins A and B. Proc. Natl. Acad. Sci. USA, 2010, 107(30), 13467-13472.
[] [PMID: 20624955]
Albesa-Jové, D.; Bertrand, T.; Carpenter, E.P.; Swain, G.V.; Lim, J.; Zhang, J.; Haire, L.F.; Vasisht, N.; Braun, V.; Lange, A.; von Eichel-Streiber, C.; Svergun, D.I.; Fairweather, N.F.; Brown, K.A. Four distinct structural domains in Clostridioides difficile toxin B visualized us-ing SAXS. J. Mol. Biol., 2010, 396(5), 1260-1270.
[] [PMID: 20070948]
Chen, P.; Lam, K.H.; Liu, Z.; Mindlin, F.A.; Chen, B.; Gutierrez, C.B.; Huang, L.; Zhang, Y.; Hamza, T.; Feng, H.; Matsui, T.; Bowen, M.E.; Perry, K.; Jin, R. Structure of the full-length Clostridioides difficile toxin B. Nat. Struct. Mol. Biol., 2019, 26(8), 712-719.
[] [PMID: 31308519]
Howell, M.; Green, R.; Killeen, A.; Wedderburn, L.; Picascio, V.; Rabionet, A.; Peng, Z.; Larina, M.; Xue, B.; Kurgan, L.; Uversky, V.N. Not that rigid midgets and not so flexible giants: On the abundance and roles of intrinsic disorder in short and long proteins. J. Biol. Syst., 2012, 20(04), 471-511.
Drudy, D.; Fanning, S.; Kyne, L. Toxin A-negative, toxin B-positive Clostridioides difficile. Int. J. Infect. Dis., 2007, 11(1), 5-10.
[] [PMID: 16857405]
Savidge, T.C.; Pan, W.H.; Newman, P.; O’brien, M.; Anton, P.M.; Pothoulakis, C. Clostridioides difficile toxin B is an inflammatory entero-toxin in human intestine. Gastroenterology, 2003, 125(2), 413-420.
[] [PMID: 12891543]
Savidge, T.C.; Urvil, P.; Oezguen, N.; Ali, K.; Choudhury, A.; Acharya, V.; Pinchuk, I.; Torres, A.G.; English, R.D.; Wiktorowicz, J.E.; Loeffelholz, M.; Kumar, R.; Shi, L.; Nie, W.; Braun, W.; Herman, B.; Hausladen, A.; Feng, H.; Stamler, J.S.; Pothoulakis, C. Host S-nitrosylation inhibits clostridial small molecule-activated glucosylating toxins. Nat. Med., 2011, 17(9), 1136-1141.
[] [PMID: 21857653]
Kreimeyer, I.; Euler, F.; Marckscheffel, A.; Tatge, H.; Pich, A.; Olling, A.; Schwarz, J.; Just, I.; Gerhard, R. Autoproteolytic cleavage medi-ates cytotoxicity of Clostridioides difficile toxin A. Naunyn Schmiedebergs Arch. Pharmacol., 2011, 383(3), 253-262.
[] [PMID: 21046073]
Chumbler, N.M.; Farrow, M.A.; Lapierre, L.A.; Franklin, J.L.; Haslam, D.B.; Goldenring, J.R.; Lacy, D.B. Clostridioides difficile Toxin B causes epithelial cell necrosis through an autoprocessing-independent mechanism. PLoS Pathog., 2012, 8(12), e1003072.
[] [PMID: 23236283]
Li, S.; Shi, L.; Yang, Z.; Feng, H. Cytotoxicity of Clostridioides difficile toxin B does not require cysteine protease-mediated autocleavage and release of the glucosyltransferase domain into the host cell cytosol. Pathog. Dis., 2013, 67(1), 11-18.
[] [PMID: 23620115]
Li, S.; Shi, L.; Yang, Z.; Zhang, Y.; Perez-Cordon, G.; Huang, T.; Ramsey, J.; Oezguen, N.; Savidge, T.C.; Feng, H. Critical roles of Clos-tridioides difficile toxin B enzymatic activities in pathogenesis. Infect. Immun., 2015, 83(2), 502-513.
[] [PMID: 25404023]
Olling, A.; Hüls, C.; Goy, S.; Müller, M.; Krooss, S.; Rudolf, I.; Tatge, H.; Gerhard, R. The combined repetitive oligopeptides of Clostridi-oides difficile toxin A counteract premature cleavage of the glucosyl-transferase domain by stabilizing protein conformation. Toxins (Basel), 2014, 6(7), 2162-2176.
[] [PMID: 25054784]
Zhang, Y.; Hamza, T.; Gao, S.; Feng, H. Masking autoprocessing of Clostridioides difficile toxin A by the C-terminus combined repetitive oligo peptides. Biochem. Biophys. Res. Commun., 2015, 459(2), 259-263.
[] [PMID: 25725153]
Obradovic, Z.; Peng, K.; Vucetic, S.; Radivojac, P.; Dunker, A.K. Exploiting heterogeneous sequence properties improves prediction of protein disorder. Proteins, 2005, 61(S7)(Suppl. 7), 176-182.
[] [PMID: 16187360]
Ishida, T.; Kinoshita, K. PrDOS: Prediction of disordered protein regions from amino acid sequence. Nucleic Acids Res, 2007, 35 (Web Server), W460-W464.
Walsh, I.; Martin, A.J.; Di Domenico, T.; Tosatto, S.C. ESpritz: Accurate and fast prediction of protein disorder. Bioinformatics, 2012, 28(4), 503-509.
[] [PMID: 22190692]
Andreeva, A.; Howorth, D.; Brenner, S.E.; Hubbard, T.J.; Chothia, C.; Murzin, A.G. SCOP database in 2004: Refinements integrate struc-ture and sequence family data. Nucleic Acids Res., 2004, 32(Database issue), D226-D229.
[] [PMID: 14681400]
Murzin, A.G.; Brenner, S.E.; Hubbard, T.; Chothia, C. SCOP: A structural classification of proteins database for the investigation of se-quences and structures. J. Mol. Biol., 1995, 247(4), 536-540.
[] [PMID: 7723011]
de Lima Morais, D.A.; Fang, H.; Rackham, O.J.; Wilson, D.; Pethica, R.; Chothia, C.; Gough, J. SUPERFAMILY 1.75 including a domain-centric gene ontology method. Nucleic Acids Res., 2011, 39(Database issue), D427-D434.
[] [PMID: 21062816]
Mészáros, B.; Simon, I.; Dosztányi, Z. Prediction of protein binding regions in disordered proteins. PLOS Comput. Biol., 2009, 5(5), e1000376.
[] [PMID: 19412530]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy