Abstract
Intrinsically disordered proteins (IDPs) are either entirely disordered or contain disordered regions in their native state. IDPs were found to be abundant across all kingdoms of life, particularly in eukaryotes, and are implicated in numerous cellular processes. Experimental annotation of disorder lags behind the rapidly growing sizes of the protein databases and thus computational methods are used to close this gap and to investigate the disorder. MFDp2 is a novel webserver for accurate sequence-based prediction of protein disorder which also outputs well-described sequence-derived information that allows profiling the predicted disorder. We conveniently visualize sequence conservation, predicted secondary structure, relative solvent accessibility, and alignments to chains with annotated disorder. The webserver allows predictions for multiple proteins at the same time, includes help pages and tutorial, and the results can be downloaded as text-based (parsable) file. MFDp2 is freely available at http://biomine.ece.ualberta.ca/MFDp2/.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Uversky VN, Gillespie JR, Fink AL (2000) Why are “natively unfolded” proteins unstructured under physiologic conditions? Proteins 41:415–427
Uversky VN (2002) Natively unfolded proteins: a point where biology waits for physics. Protein Sci 11:739–756
Dunker AK, Oldfield CJ, Meng J, Romero P, Yang JY, Chen JW, Vacic V, Obradovic Z, Uversky VN (2008) The unfoldomics decade: an update on intrinsically disordered proteins. BMC Genomics 9 Suppl 2:S1
Peng Z, Xue B, Kurgan L, Uversky VN (2013) Resilience of death: intrinsic disorder in proteins involved in the programmed cell death. Cell Death Differ 20(9):1257–1267
Peng Z, Mizianty MJ, Xue B, Kurgan L, Uversky VN (2012) More than just tails: intrinsic disorder in histone proteins. Mol Biosyst 8:1886–1901
Russell RB, Gibson TJ (2008) A careful disorderliness in the proteome: sites for interaction and targets for future therapies. FEBS Lett 582:1271–1275
Uversky VN, Oldfield CJ, Midic U, Xie H, Xue B, Vucetic S, Iakoucheva LM, Obradovic Z, Dunker AK (2009) Unfoldomics of human diseases: linking protein intrinsic disorder with diseases. BMC Genomics 10 Suppl 1:S7
Uversky VN, Oldfield CJ, Dunker AK (2008) Intrinsically disordered proteins in human diseases: introducing the D2 concept. Annu Rev Biophys 37:215–246
Xue B, Mizianty MJ, Kurgan LA, Uversky VN (2012) Protein intrinsic disorder as a flexible armor and a weapon of HIV-1. Cell Mol Life Sci 69(8):1211–1259
Iakoucheva LM, Brown CJ, Lawson JD, Obradovic Z, Dunker AK (2002) Intrinsic disorder in cell-signaling and cancer-associated proteins. J Mol Biol 323:573–584
Cheng Y, LeGall T, Oldfield CJ, Dunker AK, Uversky VN (2006) Abundance of intrinsic disorder in protein associated with cardiovascular disease. Biochemistry 45:10448–10460
Raychaudhuri S, Dey S, Bhattacharyya NP, Mukhopadhyay D (2009) The role of intrinsically unstructured proteins in neurodegenerative diseases. PLoS One 4:e5566
Uversky VN (2009) Intrinsic disorder in proteins associated with neurodegenerative diseases. Front Biosci 14:5188–5238
Midic U, Oldfield CJ, Dunker AK, Obradovic Z, Uversky VN (2009) Protein disorder in the human diseasome: unfoldomics of human genetic diseases. BMC Genomics 10 Suppl 1:S12
Uversky VN (2008) Amyloidogenesis of natively unfolded proteins. Curr Alzheimer Res 5:260–287
Ward JJ, Sodhi JS, McGuffin LJ, Buxton BF, Jones DT (2004) Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J Mol Biol 337:635–645
Xue B, Dunker AK, Uversky VN (2012) Orderly order in protein intrinsic disorder distribution: disorder in 3500 proteomes from viruses and the three domains of life. J Biomol Struct Dyn 30:137–149
Pancsa R, Tompa P (2012) Structural disorder in eukaryotes. PLoS One 7:e34687
Yan J, Mizianty MJ, Filipow PL, Uversky VN, Kurgan L (2013) RAPID: fast and accurate sequence-based prediction of intrinsic disorder content on proteomic scale. Biochim Biophys Acta 1834:1671–1680
Peng Z, Mizianty MJ, Kurgan L (2013) Genome-scale prediction of proteins with long intrinsically disordered regions. Proteins Struct Funct Bioinformatics
Mizianty MJ, Peng Z, Kurgan L (2013) MFDp2: accurate predictor of disorder in proteins by fusion of disorder probabilities, content and profiles. Intrinsically Disordered Proteins 1:13–22
Deng X, Eickholt J, Cheng J (2012) A comprehensive overview of computational protein disorder prediction methods. Mol Biosyst 8:114–121
Peng Z-L, Kurgan LA (2012) Comprehensive comparative assessment of in-silico predictors of disordered regions. Curr Protein Pept Sci 13:6–18
He B, Wang K, Liu Y, Xue B, Uversky VN, Dunker AK (2009) Predicting intrinsic disorder in proteins: an overview. Cell Res 19:929–949
Mizianty MJ, Stach W, Chen K, Kedarisetti KD, Disfani FM, Kurgan LA (2010) Improved sequence-based prediction of disordered regions with multilayer fusion of multiple information sources. Bioinformatics 26:i489–i496
Mizianty MJ, Zhang T, Xue B, Zhou Y, Dunker AK, Uversky VN, Kurgan LA (2011) In-silico prediction of disorder content using hybrid sequence representation. BMC Bioinformatics 12:245
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The Protein Data Bank. Nucleic Acids Res 28:235–242
Sickmeier M, Hamilton JA, LeGall T, Vacic V, Cortese MS, Tantos A, Szabo B, Tompa P, Chen J, Uversky VN et al (2007) DisProt: the database of disordered proteins. Nucleic Acids Res 35:D786–D793
McGuffin LJ, Bryson K, Jones DT (2000) The PSIPRED protein structure prediction server. Bioinformatics 16:404–405
Faraggi E, Xue B, Zhou Y (2009) Improving the prediction accuracy of residue solvent accessibility and real-value backbone torsion angles of proteins by guided-learning through a two-layer neural network. Proteins 74:847–856
Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25:3389–3402
Wang K, Samudrala R (2006) Incorporating background frequency improves entropy-based residue conservation measures. BMC Bioinformatics 7:385
Zur Hausen H (2002) Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2:342–350
Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM (1990) The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63:1129–1136
Scheffner M, Huibregtse JM, Vierstra RD, Howley PM (1993) The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75:495–505
Patel D, Huang SM, Baglia LA, McCance DJ (1999) The E6 protein of human papillomavirus type 16 binds to and inhibits co-activation by CBP and p300. EMBO J 18:5061–5072
Zimmermann H, Degenkolbe R, Bernard HU, O’Connor MJ (1999) The human papillomavirus type 16 E6 oncoprotein can down-regulate p53 activity by targeting the transcriptional coactivator CBP/p300. J Virol 73:6209–6219
Kumar A, Zhao Y, Meng G, Zeng M, Srinivasan S, Delmolino LM, Gao Q, Dimri G, Weber GF, Wazer DE et al (2002) Human papillomavirus oncoprotein E6 inactivates the transcriptional coactivator human ADA3. Mol Cell Biol 22:5801–5812
Gross-Mesilaty S, Reinstein E, Bercovich B, Tobias KE, Schwartz AL, Kahana C, Ciechanover A (1998) Basal and human papillomavirus E6 oncoprotein-induced degradation of Myc proteins by the ubiquitin pathway. Proc Natl Acad Sci USA 95:8058–8063
Ronco LV, Karpova AY, Vidal M, Howley PM (1998) Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Genes Dev 12:2061–2072
Kukimoto I, Aihara S, Yoshiike K, Kanda T (1998) Human papillomavirus oncoprotein E6 binds to the C-terminal region of human minichromosome maintenance 7 protein. Biochem Biophys Res Commun 249:258–262
Srivenugopal KS, Ali-Osman F (2002) The DNA repair protein, O(6)-methylguanine-DNA methyltransferase is a proteolytic target for the E6 human papillomavirus oncoprotein. Oncogene 21:5940–5945
Gao Q, Kumar A, Srinivasan S, Singh L, Mukai H, Ono Y, Wazer DE, Band V (2000) PKN binds and phosphorylates human papillomavirus E6 oncoprotein. J Biol Chem 275:14824–14830
Li S, Labrecque S, Gauzzi MC, Cuddihy AR, Wong AH, Pellegrini S, Matlashewski GJ, Koromilas AE (1999) The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-alpha. Oncogene 18:5727–5737
Gao Q, Srinivasan S, Boyer SN, Wazer DE, Band V (1999) The E6 oncoproteins of high-risk papillomaviruses bind to a novel putative GAP protein, E6TP1, and target it for degradation. Mol Cell Biol 19:733–744
Filippova M, Song H, Connolly JL, Dermody TS, Duerksen-Hughes PJ (2002) The human papillomavirus 16 E6 protein binds to tumor necrosis factor (TNF) R1 and protects cells from TNF-induced apoptosis. J Biol Chem 277:21730–21739
Thomas M, Banks L (1999) Human papillomavirus (HPV) E6 interactions with Bak are conserved amongst E6 proteins from high and low risk HPV types. J Gen Virol 80(Pt 6):1513–1517
Tong X, Boll W, Kirchhausen T, Howley PM (1998) Interaction of the bovine papillomavirus E6 protein with the clathrin adaptor complex AP-1. J Virol 72:476–482
Chen JJ, Reid CE, Band V, Androphy EJ (1995) Interaction of papillomavirus E6 oncoproteins with a putative calcium-binding protein. Science 269:529–531
Du M, Fan X, Hong E, Chen JJ (2002) Interaction of oncogenic papillomavirus E6 proteins with fibulin-1. Biochem Biophys Res Commun 296:962–969
Kiyono T, Hiraiwa A, Fujita M, Hayashi Y, Akiyama T, Ishibashi M (1997) Binding of high-risk human papillomavirus E6 oncoproteins to the human homologue of the Drosophila discs large tumor suppressor protein. Proc Natl Acad Sci USA 94:11612–11616
Nakagawa S, Huibregtse JM (2000) Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase. Mol Cell Biol 20:8244–8253
Glaunsinger BA, Lee SS, Thomas M, Banks L, Javier R (2000) Interactions of the PDZ-protein MAGI-1 with adenovirus E4-ORF1 and high-risk papillomavirus E6 oncoproteins. Oncogene 19:5270–5280
Lee SS, Glaunsinger B, Mantovani F, Banks L, Javier RT (2000) Multi-PDZ domain protein MUPP1 is a cellular target for both adenovirus E4-ORF1 and high-risk papillomavirus type 18 E6 oncoproteins. J Virol 74:9680–9693
Sedman SA, Barbosa MS, Vass WC, Hubbert NL, Haas JA, Lowy DR, Schiller JT (1991) The full-length E6 protein of human papillomavirus type 16 has transforming and trans-activating activities and cooperates with E7 to immortalize keratinocytes in culture. J Virol 65:4860–4866
Morosov A, Phelps WC, Raychaudhuri P (1994) Activation of the c-fos gene by the HPV16 oncoproteins depends upon the cAMP-response element at -60. J Biol Chem 269:18434–18440
Dey A, Atcha IA, Bagchi S (1997) HPV16 E6 oncoprotein stimulates the transforming growth factor-beta 1 promoter in fibroblasts through a specific GC-rich sequence. Virology 228:190–199
Gewin L, Galloway DA (2001) E box-dependent activation of telomerase by human papillomavirus type 16 E6 does not require induction of c-myc. J Virol 75:7198–7201
Oh ST, Kyo S, Laimins LA (2001) Telomerase activation by human papillomavirus type 16 E6 protein: induction of human telomerase reverse transcriptase expression through Myc and GC-rich Sp1 binding sites. J Virol 75:5559–5566
Ristriani T, Masson M, Nominé Y, Laurent C, Lefevre JF, Weiss E, Travé G (2000) HPV oncoprotein E6 is a structure-dependent DNA-binding protein that recognizes four-way junctions. J Mol Biol 296:1189–1203
Ristriani T, Nominé Y, Masson M, Weiss E, Travé G (2001) Specific recognition of four-way DNA junctions by the C-terminal zinc-binding domain of HPV oncoprotein E6. J Mol Biol 305:729–739
Li X, Coffino P (1996) High-risk human papillomavirus E6 protein has two distinct binding sites within p53, of which only one determines degradation. J Virol 70:4509–4516
Thomas MC, Chiang C-M (2005) E6 oncoprotein represses p53-dependent gene activation via inhibition of protein acetylation independently of inducing p53 degradation. Mol Cell 17:251–264
Cole ST, Danos O (1987) Nucleotide sequence and comparative analysis of the human papillomavirus type 18 genome. Phylogeny of papillomaviruses and repeated structure of the E6 and E7 gene products. J Mol Biol 193:599–608
Pim D, Storey A, Thomas M, Massimi P, Banks L (1994) Mutational analysis of HPV-18 E6 identifies domains required for p53 degradation in vitro, abolition of p53 transactivation in vivo and immortalisation of primary BMK cells. Oncogene 9:1869–1876
Thomas M, Pim D, Banks L (1999) The role of the E6-p53 interaction in the molecular pathogenesis of HPV. Oncogene 18:7690–7700
Nominé Y, Ristriani T, Laurent C, Lefèvre JF, Weiss E, Travé G (2001) Formation of soluble inclusion bodies by hpv e6 oncoprotein fused to maltose-binding protein. Protein Expr Purif 23:22–32
Nominé Y, Charbonnier S, Ristriani T, Stier G, Masson M, Cavusoglu N, Van Dorsselaer A, Weiss E, Kieffer B, Travé G (2003) Domain substructure of HPV E6 oncoprotein: biophysical characterization of the E6 C-terminal DNA-binding domain. Biochemistry 42:4909–4917
Zanier K, ould M’hamed ould Sidi A, Boulade-Ladame C, Rybin V, Chappelle A, Atkinson A, Kieffer B, Travé G (2012) Solution structure analysis of the HPV16 E6 oncoprotein reveals a self-association mechanism required for E6-mediated degradation of p53. Structure 20:604–617
Uversky VN, Roman A, Oldfield CJ, Dunker AK (2006) Protein intrinsic disorder and human papillomaviruses: increased amount of disorder in E6 and E7 oncoproteins from high risk HPVs. J Proteome Res 5:1829–1842
Xue B, Ganti K, Rabionet A, Banks L, Uversky VN (2013) Disordered interactome of human papillomavirus. Curr Pharm Des
Salmena L, Carracedo A, Pandolfi PP (2008) Tenets of PTEN tumor suppression. Cell 133:403–414
Maehama T, Dixon JE (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273:13375–13378
Zhang XC, Piccini A, Myers MP, Van Aelst L, Tonks NK (2012) Functional analysis of the protein phosphatase activity of PTEN. Biochem J 444:457–464
Shen WH, Balajee AS, Wang J, Wu H, Eng C, Pandolfi PP, Yin Y (2007) Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128:157–170
Waite KA, Eng C (2002) Protean PTEN: form and function. Am J Hum Genet 70:829–844
Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM, Cordon-Cardo C, Catoretti G, Fisher PE, Parsons R (1999) Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci USA 96:1563–1568
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R et al (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947
Fraser MM, Zhu X, Kwon C-H, Uhlmann EJ, Gutmann DH, Baker SJ (2004) Pten loss causes hypertrophy and increased proliferation of astrocytes in vivo. Cancer Res 64:7773–7779
Das S, Dixon JE, Cho W (2003) Membrane-binding and activation mechanism of PTEN. Proc Natl Acad Sci USA 100:7491–7496
Walker SM, Leslie NR, Perera NM, Batty IH, Downes CP (2004) The tumour-suppressor function of PTEN requires an N-terminal lipid-binding motif. Biochem J 379:301–307
Lee JO, Yang H, Georgescu MM, Di Cristofano A, Maehama T, Shi Y, Dixon JE, Pandolfi P, Pavletich NP (1999) Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell 99:323–334
Rahdar M, Inoue T, Meyer T, Zhang J, Vazquez F, Devreotes PN (2009) A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN. Proc Natl Acad Sci USA 106:480–485
Vazquez F, Ramaswamy S, Nakamura N, Sellers WR (2000) Phosphorylation of the PTEN tail regulates protein stability and function. Mol Cell Biol 20:5010–5018
Ross AH, Gericke A (2009) Phosphorylation keeps PTEN phosphatase closed for business. Proc Natl Acad Sci USA 106:1297–1298
Acknowledgments
This work was supported by the Dissertation fellowship awarded by the University of Alberta to M.J.M. and by the Discovery grant from the Natural Sciences and Engineering Research Council of Canada to L.K.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media New York
About this protocol
Cite this protocol
Mizianty, M.J., Uversky, V., Kurgan, L. (2014). Prediction of Intrinsic Disorder in Proteins Using MFDp2. In: Kihara, D. (eds) Protein Structure Prediction. Methods in Molecular Biology, vol 1137. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0366-5_11
Download citation
DOI: https://doi.org/10.1007/978-1-4939-0366-5_11
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-0365-8
Online ISBN: 978-1-4939-0366-5
eBook Packages: Springer Protocols