Prediction of intrinsic disorder in proteins using MFDp2.

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/.

[1]  K. Srivenugopal,et al.  The DNA repair protein, O6-Methylguanine-DNA methyltransferase is a proteolytic target for the E6 human papillomavirus oncoprotein , 2002, Oncogene.

[2]  A. Cuddihy,et al.  The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-α , 1999, Oncogene.

[3]  Vladimir N Uversky,et al.  Intrinsic disorder in proteins associated with neurodegenerative diseases. , 2009, Frontiers in bioscience.

[4]  Liam J. McGuffin,et al.  The PSIPRED protein structure prediction server , 2000, Bioinform..

[5]  A. Dunker,et al.  Predicting intrinsic disorder in proteins: an overview , 2009, Cell Research.

[6]  Jianlin Cheng,et al.  A comprehensive overview of computational protein disorder prediction methods. , 2012, Molecular bioSystems.

[7]  T. Kirchhausen,et al.  Interaction of the Bovine Papillomavirus E6 Protein with the Clathrin Adaptor Complex AP-1 , 1998, Journal of Virology.

[8]  H. Hausen Papillomaviruses and cancer: from basic studies to clinical application , 2002, Nature Reviews Cancer.

[9]  I. Batty,et al.  The tumour-suppressor function of PTEN requires an N-terminal lipid-binding motif. , 2004, The Biochemical journal.

[10]  Tomohiko Maehama,et al.  The Tumor Suppressor, PTEN/MMAC1, Dephosphorylates the Lipid Second Messenger, Phosphatidylinositol 3,4,5-Trisphosphate* , 1998, The Journal of Biological Chemistry.

[11]  D. Lowy,et al.  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 , 1991, Journal of virology.

[12]  Wonhwa Cho,et al.  Membrane-binding and activation mechanism of PTEN , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[13]  A. Dunker,et al.  Abundance of intrinsic disorder in protein associated with cardiovascular disease. , 2006, Biochemistry.

[14]  A. Ciechanover,et al.  Basal and human papillomavirus E6 oncoprotein-induced degradation of Myc proteins by the ubiquitin pathway. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[15]  A. Cuddihy,et al.  The human papilloma virus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-alpha. , 1999, Oncogene.

[16]  Lukasz A. Kurgan,et al.  Improved sequence-based prediction of disordered regions with multilayer fusion of multiple information sources , 2010, Bioinform..

[17]  Lukasz Kurgan,et al.  RAPID: fast and accurate sequence-based prediction of intrinsic disorder content on proteomic scale. , 2013, Biochimica et biophysica acta.

[18]  Miranda Thomas,et al.  Interactions of the PDZ-protein MAGI-1 with adenovirus E4-ORF1 and high-risk papillomavirus E6 oncoproteins , 2000, Oncogene.

[19]  Lukasz Kurgan,et al.  Comprehensive comparative assessment of in-silico predictors of disordered regions. , 2012, Current protein & peptide science.

[20]  Miranda Thomas,et al.  Human papillomavirus (HPV) E6 interactions with Bak are conserved amongst E6 proteins from high and low risk HPV types. , 1999, The Journal of general virology.

[21]  D. Galloway,et al.  E Box-Dependent Activation of Telomerase by Human Papillomavirus Type 16 E6 Does Not Require Induction of c-myc , 2001, Journal of Virology.

[22]  C. Cordon-Cardo,et al.  Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[23]  A. Dey,et al.  HPV16 E6 oncoprotein stimulates the transforming growth factor-beta 1 promoter in fibroblasts through a specific GC-rich sequence. , 1997, Virology.

[24]  Ajay Mahaputra Kumar,et al.  PKN Binds and Phosphorylates Human Papillomavirus E6 Oncoprotein* , 2000, The Journal of Biological Chemistry.

[25]  X. Li,et al.  High-risk human papillomavirus E6 protein has two distinct binding sites within p53, of which only one determines degradation , 1996, Journal of virology.

[26]  Goberdhan P Dimri,et al.  Human Papillomavirus Oncoprotein E6 Inactivates the Transcriptional Coactivator Human ADA3 , 2002, Molecular and Cellular Biology.

[27]  C. Eng,et al.  Protean PTEN: form and function. , 2002, American journal of human genetics.

[28]  V. Uversky,et al.  Disordered interactome of human papillomavirus. , 2014, Current pharmaceutical design.

[29]  Miranda Thomas,et al.  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. , 1994, Oncogene.

[30]  T. Gibson,et al.  A careful disorderliness in the proteome: Sites for interaction and targets for future therapies , 2008, FEBS letters.

[31]  A Keith Dunker,et al.  Protein intrinsic disorder and human papillomaviruses: increased amount of disorder in E6 and E7 oncoproteins from high risk HPVs. , 2006, Journal of proteome research.

[32]  D. Patel,et al.  The E6 protein of human papillomavirus type 16 binds to and inhibits co‐activation by CBP and p300 , 1999, The EMBO journal.

[33]  Lukasz Kurgan,et al.  Protein intrinsic disorder as a flexible armor and a weapon of HIV-1 , 2011, Cellular and Molecular Life Sciences.

[34]  Lukasz Kurgan,et al.  MFDp2: Accurate predictor of disorder in proteins by fusion of disorder probabilities, content and profiles. , 2013, Intrinsically disordered proteins.

[35]  Etienne Weiss,et al.  Domain substructure of HPV E6 oncoprotein: biophysical characterization of the E6 C-terminal DNA-binding domain. , 2003, Biochemistry.

[36]  P. Pandolfi,et al.  Essential Role for Nuclear PTEN in Maintaining Chromosomal Integrity , 2007, Cell.

[37]  A. Gericke,et al.  Phosphorylation keeps PTEN phosphatase closed for business , 2009, Proceedings of the National Academy of Sciences.

[38]  P. Tompa,et al.  Structural Disorder in Eukaryotes , 2012, PloS one.

[39]  M. Wigler,et al.  PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer , 1997, Science.

[40]  S. Cole,et al.  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. , 1987, Journal of molecular biology.

[41]  F. Vazquez,et al.  A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN , 2009, Proceedings of the National Academy of Sciences.

[42]  M. Vidal,et al.  Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. , 1998, Genes & development.

[43]  E. Androphy,et al.  Interaction of papillomavirus E6 oncoproteins with a putative calcium-binding protein. , 1995, Science.

[44]  Jason J Chen,et al.  Interaction of oncogenic papillomavirus E6 proteins with fibulin-1. , 2002, Biochemical and biophysical research communications.

[45]  Yaoqi Zhou,et al.  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 , 2009, Proteins.

[46]  Lukasz Kurgan,et al.  More than just tails: intrinsic disorder in histone proteins. , 2012, Molecular bioSystems.

[47]  Lukasz A. Kurgan,et al.  In-silico prediction of disorder content using hybrid sequence representation , 2011, BMC Bioinformatics.

[48]  A Keith Dunker,et al.  Protein disorder in the human diseasome: unfoldomics of human genetic diseases , 2009, BMC Genomics.

[49]  E. Weiss,et al.  Specific recognition of four-way DNA junctions by the C-terminal zinc-binding domain of HPV oncoprotein E6. , 2001, Journal of molecular biology.

[50]  A Keith Dunker,et al.  Unfoldomics of human diseases: linking protein intrinsic disorder with diseases , 2009, BMC Genomics.

[51]  J. Lefèvre,et al.  Formation of soluble inclusion bodies by hpv e6 oncoprotein fused to maltose-binding protein. , 2001, Protein expression and purification.

[52]  J. S. Sodhi,et al.  Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. , 2004, Journal of molecular biology.

[53]  Debashis Mukhopadhyay,et al.  The Role of Intrinsically Unstructured Proteins in Neurodegenerative Diseases , 2009, PloS one.

[54]  Miranda Thomas,et al.  The role of the E6-p53 interaction in the molecular pathogenesis of HPV , 1999, Oncogene.

[55]  P. Raychaudhuri,et al.  Activation of the c-fos gene by the HPV16 oncoproteins depends upon the cAMP-response element at -60. , 1994, The Journal of biological chemistry.

[56]  Arnold J. Levine,et al.  The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53 , 1990, Cell.

[57]  Thomas L. Madden,et al.  Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. , 1997, Nucleic acids research.

[58]  Xiaoqun Zhang,et al.  Functional analysis of the protein phosphatase activity of PTEN , 2012, The Biochemical journal.

[59]  Christopher J. Oldfield,et al.  Intrinsically disordered proteins in human diseases: introducing the D2 concept. , 2008, Annual review of biophysics.

[60]  V. Uversky Natively unfolded proteins: A point where biology waits for physics , 2002, Protein science : a publication of the Protein Society.

[61]  L. Iakoucheva,et al.  Intrinsic disorder in cell-signaling and cancer-associated proteins. , 2002, Journal of molecular biology.

[62]  C. Chiang,et al.  E6 oncoprotein represses p53-dependent gene activation via inhibition of protein acetylation independently of inducing p53 degradation. , 2005, Molecular cell.

[63]  J. Huibregtse,et al.  Human Scribble (Vartul) Is Targeted for Ubiquitin-Mediated Degradation by the High-Risk Papillomavirus E6 Proteins and the E6AP Ubiquitin-Protein Ligase , 2000, Molecular and Cellular Biology.

[64]  T. Kanda,et al.  Human papillomavirus oncoprotein E6 binds to the C-terminal region of human minichromosome maintenance 7 protein. , 1998, Biochemical and biophysical research communications.

[65]  Lukasz Kurgan,et al.  Genome‐scale prediction of proteins with long intrinsically disordered regions , 2014, Proteins.

[66]  Helen Song,et al.  The Human Papillomavirus 16 E6 Protein Binds to Tumor Necrosis Factor (TNF) R1 and Protects Cells from TNF-induced Apoptosis* , 2002, The Journal of Biological Chemistry.

[67]  L. Banks,et al.  Multi-PDZ Domain Protein MUPP1 Is a Cellular Target for both Adenovirus E4-ORF1 and High-Risk Papillomavirus Type 18 E6 Oncoproteins , 2000, Journal of Virology.

[68]  J. Lefèvre,et al.  HPV oncoprotein E6 is a structure-dependent DNA-binding protein that recognizes four-way junctions. , 2000, Journal of molecular biology.

[69]  Zoran Obradovic,et al.  DisProt: the Database of Disordered Proteins , 2006, Nucleic Acids Res..

[70]  M Fujita,et al.  Binding of high-risk human papillomavirus E6 oncoproteins to the human homologue of the Drosophila discs large tumor suppressor protein. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[71]  V. Rybin,et al.  Solution structure analysis of the HPV16 E6 oncoprotein reveals a self-association mechanism required for E6-mediated degradation of p53. , 2012, Structure.

[72]  Lukasz Kurgan,et al.  Resilience of death: intrinsic disorder in proteins involved in the programmed cell death , 2013, Cell Death and Differentiation.

[73]  Vladimir N Uversky,et al.  Amyloidogenesis of natively unfolded proteins. , 2008, Current Alzheimer research.

[74]  A. Dunker,et al.  Orderly order in protein intrinsic disorder distribution: disorder in 3500 proteomes from viruses and the three domains of life , 2012, Journal of biomolecular structure & dynamics.

[75]  Francisca Vazquez,et al.  Phosphorylation of the PTEN Tail Regulates Protein Stability and Function , 2000, Molecular and Cellular Biology.

[76]  Christopher J. Oldfield,et al.  The unfoldomics decade: an update on intrinsically disordered proteins , 2008, BMC Genomics.

[77]  V. Uversky,et al.  Why are “natively unfolded” proteins unstructured under physiologic conditions? , 2000, Proteins.

[78]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[79]  L. Laimins,et al.  Telomerase Activation by Human Papillomavirus Type 16 E6 Protein: Induction of Human Telomerase Reverse Transcriptase Expression through Myc and GC-Rich Sp1 Binding Sites , 2001, Journal of Virology.

[80]  D. Gutmann,et al.  Pten Loss Causes Hypertrophy and Increased Proliferation of Astrocytes In vivo , 2004, Cancer Research.

[81]  Pier Paolo Pandolfi,et al.  Tenets of PTEN Tumor Suppression , 2008, Cell.

[82]  Tomohiko Maehama,et al.  Crystal Structure of the PTEN Tumor Suppressor Implications for Its Phosphoinositide Phosphatase Activity and Membrane Association , 1999, Cell.

[83]  Kai Wang,et al.  Incorporating background frequency improves entropy-based residue conservation measures , 2006, BMC Bioinform..

[84]  M. Scheffner,et al.  The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53 , 1993, Cell.

[85]  M. O’Connor,et al.  The Human Papillomavirus Type 16 E6 Oncoprotein Can Down-Regulate p53 Activity by Targeting the Transcriptional Coactivator CBP/p300 , 1999, Journal of Virology.