Insights into the regulation of intrinsically disordered proteins in the human proteome by analyzing sequence and gene expression data

Genome Biology

Volumn 10, Issue 5, 2009, Pages

  Edwards, Yvonne J K ^a   Lobley, Anna E ^a   Pentony, Melissa M ^a   Jones, David T ^a  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

DISORDERED PROTEIN; MESSENGER RNA; MICRORNA; PROTEOME; UNCLASSIFIED DRUG;

ARTICLE; CELL PROTECTION; CONTROLLED STUDY; GENE EXPRESSION REGULATION; GENETIC TRANSCRIPTION; HUMAN; HUMAN CELL; PROTEIN FOLDING; PROTEIN STABILITY; PROTEIN STRUCTURE; REGULATORY MECHANISM; RNA DEGRADATION; SEQUENCE ANALYSIS; SIGNAL TRANSDUCTION; UBIQUITINATION; GENE EXPRESSION PROFILING; METABOLISM; RNA STABILITY;

GENE EXPRESSION PROFILING; HUMANS; MICRORNAS; PROTEIN FOLDING; PROTEIN STABILITY; PROTEOME; RNA STABILITY; UBIQUITINATION;

EID: 66749163093     PISSN: 14747596     EISSN: 1474760X     Source Type: Journal    
DOI: 10.1186/gb-2009-10-5-r50     Document Type: Article

References (113)

1. Dunker AK Lawson JD Brown CJ Williams RM Romero P Oh JS Oldfield CJ Campen AM Ratliff CM Hipps KW Ausio J Nissen MS Reeves R Kang C Kissinger CR Bailey RW Griswold MD Chiu W Garner EC Obradovic Z Intrinsically disordered protein. J Mol Graph Model 2001, 19:26-59. 10.1016/S1093-3263(00)00138-8 11381529
2. Dunker AK Brown CJ Lawson JD Iakoucheva LM Obradovic Z Intrinsic disorder and protein function. Biochemistry 2002, 41:6573-6582. 10.1021/ bi012159+ 12022860
3. Dunker AK Cortese MS Romero P Iakoucheva LM Uversky VN Flexible nets. The roles of intrinsic disorder in protein interaction networks. FEBS J 2005, 272:5129-5148. 10.1111/j.1742-4658.2005.04948.x 16218947
4. Uversky VN Oldfield CJ Dunker AK Showing your ID: Intrinsic disorder as an ID for recognition, regulation and cell signaling. J Mol Recognit 2005, 18:343-384. 10.1002/jmr.747 16094605
5. Hegyi H Schad E Tompa P Structural disorder promotes assembly of protein complexes. BMC Struct Biol 2007 7 65 2194777 17922903 10.1186/ 1472-6807-7-65
6. Ward JJ Sodhi JS McGuffin LJ Buxton BF Jones DT Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J Mol Biol 2004, 337:635-645. 10.1016/ j.jmb.2004.02.002 15019783
7. Dyson HJ Wright PE Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol 2005, 6:197-208. 10.1038/nrm1589 15738986
8. Haynes C Oldfield CJ Ji F Klitgord N Cusick ME Radivojac P Uversky VN Vidal M Iakoucheva LM Intrinsic disorder is a common feature of hub proteins from four eukaryotic interactomes. PLoS Comput Biol 2006, 2:e100. 10.1371/journal.pcbi.0020100 16884331 1526461
9. Lobley A Swindells MB Orengo CA Jones DT Inferring function using patterns of native disorder in proteins. PLoS Comput Biol 2007,3:e162. 1950950 17722973 10.1371/journal.pcbi.0030162
10. Wright PE Dyson HJ Intrinsically unstructured proteins: Re-assessing the protein structure-function paradigm. J Mol Biol 1999, 293:321-331. 10.1006/jmbi.1999.3110 10550212
11. Uversky VN Gillespie JR Fink AL Why are "natively unfolded" proteins unstructured under physiologic conditions? Proteins 2000, 41:415-427. 10.1002/ 1097-0134(20001115)41:3<415::AID-PROT130>3.0.CO;2-7 11025552
12. Dunker AK Obradovic Z The protein trinity - linking function and disorder. Nat Biotechnol 2001, 19:805-806. 10.1038/nbt0901-805 11533628
13. Tompa P Intrinsically unstructured proteins. Trends Biochem Sci 2002, 27:527-533. 10.1016/S0968-0004(02)02169-2 12368089
14. Uversky VN Natively unfolded proteins: A point where biology waits for physics. Protein Sci 2002, 11:739-756. 2373528 11910019 10.1110/ ps.4210102
15. Uversky VN Protein folding revisited. A polypeptide chain at the folding-misfolding-nonfolding cross-roads: Which way to go? Cell Mol Life Sci 2003, 60:1852-1871. 10.1007/s00018-003-3096-6 14523548
16. Tompa P The interplay between structure and function in intrinsically unstructured proteins. FEBS Lett 2005, 579:3346-3354. 10.1016/ j.febslet.2005.03.072 15943980
17. Xie H Vucetic S Iakoucheva LM Oldfield CJ Dunker AK Obradovic Z Uversky VN Functional anthology of intrinsic disorder. 3. Ligands, post-translational modifications, and diseases associated with intrinsically disordered proteins. J Proteome Res 2007, 6:1917-1932. 2588348 17391016 10.1021/pr060394e
18. Vucetic S Xie H Iakoucheva LM Oldfield CJ Dunker AK Obradovic Z Uversky VN Functional anthology of intrinsic disorder. 2. Cellular components, domains, technical terms, developmental processes, and coding sequence diversities correlated with long disordered regions. J Proteome Res 2007, 6:1899-1916. 2588346 17391015 10.1021/pr060393m
19. Xie H Vucetic S Iakoucheva LM Oldfield CJ Dunker AK Uversky VN Obradovic Z Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions. J Proteome Res 2007, 6:1882-1898. 2543138 17391014 10.1021/pr060392u
20. Cortese MS Uversky VN Dunker AK Intrinsic disorder in scaffold proteins: getting more from less. Prog Biophys Mol Biol 2008, 98:85-106. 10.1016/ j.pbiomolbio.2008.05.007 18619997
21. Iakoucheva LM Brown CJ Lawson JD Obradovic Z Dunker AK Intrinsic disorder in cell-signaling and cancer-associated proteins. J Mol Biol 2002, 323:573-584. 10.1016/S0022-2836(02)00969-5 12381310
22. Dunker AK Obradovic Z Romero P Garner EC Brown CJ Intrinsic protein disorder in complete genomes. Genome Inform Ser Workshop Genome Inform 2000, 11:161-171. 11700597
23. Oldfield CJ Cheng Y Cortese MS Brown CJ Uversky VN Dunker AK Comparing and combining predictors of mostly disordered proteins. Biochemistry 2005, 44:1989-2000. 10.1021/bi047993o 15697224
24. Uversky VN Oldfield CJ Dunker AK Intrinsically disordered proteins in human diseases: Introducing the D2 concept. Annu Rev Biophys 2008, 37:215-246. 10.1146/annurev.biophys.37.032807.125924 18573080
25. Weinreb PH Zhen W Poon AW Conway KA Lansbury PT Jr NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. Biochemistry 1996, 35:13709-13715. 10.1021/bi961799n 8901511
26. Rochet JC Lansbury PT Jr Amyloid fibrillogenesis: Themes and variations. Curr Opin Struct Biol 2000, 10:60-68. 10.1016/S0959-440X(99)00049-4 10679462
27. Uversky VN Alpha-synuclein misfolding and neurodegenerative diseases. Curr Protein Pept Sci 2008, 9:507-540. 10.2174/138920308785915218 18855701
28. Uversky VN Amyloidogenesis of natively unfolded proteins. Curr Alzheimer Res 2008, 5:260-287. 10.2174/156720508784533312 18537543
29. Cheng Y LeGall T Oldfield CJ Dunker AK Uversky VN Abundance of intrinsic disorder in protein associated with cardiovascular disease. Biochemistry 2006, 45:10448-10460. 10.1021/bi060981d 16939197
30. Uversky VN Roman A Oldfield CJ Dunker AK Protein intrinsic disorder and human papillomaviruses: Increased amount of disorder in E6 and E7 oncoproteins from high risk HPVs. J Proteome Res 2006, 5:1829-1842. 10.1021/pr0602388 16889404
31. Galzitskaya OV Garbuzynskiy SO Lobanov MY Prediction of amyloidogenic and disordered regions in protein chains. PLoS Comput Biol 2006, 2:e177. 1761655 17196033 10.1371/journal.pcbi.0020177
32. Goldberg AL Protein degradation and protection against misfolded or damaged proteins. Nature 2003, 426:895-899. 10.1038/nature02263 14685250
33. Yang E van Nimwegen E Zavolan M Rajewsky N Schroeder M Magnasco M Darnell JE Jr Decay rates of human mRNAs: Correlation with functional characteristics and sequence attributes. Genome Res 2003, 13:1863-1872. 403777 12902380 10.1101/gr.997703
34. Raghavan A Bohjanen PR Microarray-based analyses of mRNA decay in the regulation of mammalian gene expression. Brief Funct Genomic Proteomic 2004, 3:112-124. 10.1093/bfgp/3.2.112 15355594
35. Tompa P Prilusky J Silman I Sussman JL Structural disorder serves as a weak signal for intracellular protein degradation. Proteins 2008, 71:903-909. 10.1002/prot.21773 18004785
36. Orphanides G Reinberg D A unified theory of gene expression. Cell 2002, 108:439-451. 10.1016/S0092-8674(02)00655-4 11909516
37. He L Hannon GJ MicroRNAs: Small RNAs with a big role in gene regulation. Nat Rev Genet 2004, 5:522-531. 10.1038/nrg1379 15211354
38. Bartel DP MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 2004, 116:281-297. 10.1016/S0092-8674(04)00045-5 14744438
39. Jackson RJ Standart N How do microRNAs regulate gene expression? Sci STKE 2007, 2007:rE1. 10.1126/stke.3672007re1 17200520
40. Lodish HF Zhou B Liu G Chen CZ Micromanagement of the immune system by microRNAs. Nat Rev Immunol 2008, 8:120-130. 10.1038/nri2252 18204468
41. Hobert O Gene regulation by transcription factors and microRNAs. Science 2008, 319:1785-1786. 10.1126/science.1151651 18369135
42. Ambros V The functions of animal microRNAs. Nature 2004, 431:350-355. 10.1038/nature02871 15372042
43. Krek A Grün D Poy MN Wolf R Rosenberg L Epstein EJ MacMenamin P da Piedade I Gunsalus KC Stoffel M Rajewsky N Combinatorial microRNA target predictions. Nat Genet 2005, 37:495-500. 10.1038/ng1536 15806104
44. TargetScanS. http://www.targetscan.org/
45. Lewis BP Burge CB Bartel DP Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005, 120:15-20. 10.1016/j.cell.2004.12.035 15652477
46. Grün D Wang YL Langenberger D Gunsalus KC Rajewsky N MicroRNA target predictions across seven Drosophila species and comparison to mammalian targets. PLoS Comput Biol 2005, 1:e13. 1183519 16103902 10.1371/journal.pcbi.0010013
47. Rajewsky N microRNA target predictions in animals. Nat Genet 2006, 38(Suppl):S8-S13. 10.1038/ng1798 16736023
48. Sethupathy P Corda B Hatzigeorgiou AG TarBase: A comprehensive database of experimentally supported animal microRNA targets. RNA 2006, 12:192-197. 1370898 16373484 10.1261/rna.2239606
49. Sethupathy P Megraw M Hatzigeorgiou AG A guide through present computational approaches for the identification of mammalian microRNA targets. Nat Methods 2006, 3:881-886. 10.1038/nmeth954 17060911
50. Mazière P Enright AJ Prediction of microRNA targets. Drug Discovery Today 2007, 12:452-458. 10.1016/j.drudis.2007.04.002 17532529
51. Griffiths-Jones S Saini HK van Dongen S Enright AJ miRBase: Tools for microRNA genomics. Nucleic Acids Res 2008, 36:D154-D158. 2238936 17991681 10.1093/nar/gkm952
52. Haglund K Dikic I Ubiquitylation and cell signaling. EMBO J 2005, 24:3353-3359. 1276169 16148945 10.1038/sj.emboj.7600808
53. Welchman RL Gordon C Mayer RJ Ubiquitin and ubiquitin-like proteins as multifunctional signals. Nat Rev Mol Cell Biol 2005, 6:599-609. 10.1038/ nrm1700 16064136
54. Pickart CM Fushman D Polyubiquitin chains: Polymeric protein signals. Curr Opin Chem Biol 2004, 8:610-616. 10.1016/j.cbpa.2004.09.009 15556404
55. Thrower JS Hoffman L Rechsteiner M Pickart CM Recognition of the polyubiquitin proteolytic signal. EMBO J 2000, 19:94-102. 1171781 10619848 10.1093/emboj/19.1.94
56. Salghetti SE Caudy AA Chenoweth JG Tansey WP Regulation of transcriptional activation domain function by ubiquitin. Science 2001, 293:1651-1653. 10.1126/science.1062079 11463878
57. Muratani M Tansey WP How the ubiquitin-proteasome system controls transcription. Nat Rev Mol Cell Biol 2003, 4:192-201. 10.1038/nrm1049 12612638
58. Lipford JR Deshaies RJ Diverse roles for ubiquitin-dependent proteolysis in transcriptional activation. Nat Cell Biol 2003, 5:845-850. 10.1038/ ncb1003-845 14523392
59. Molnár A Schwach F Studholme DJ Thuenemann EC Baulcombe DC miRNAs control gene expression in the single-cell alga Chlamydomonas reinhardtii. Nature 2007, 447:1126-1129. 10.1038/nature05903 17538623
60. Zhao T Li G Mi S Li S Hannon GJ Wang XJ Qi Y A complex system of small RNAs in the unicellular green alga Chlamydomonas reinhardtii. Genes Dev 2007, 21:1190-1203. 1865491 17470535 10.1101/gad.1543507
61. Ha BH Kim EE Structures of proteases for ubiqutin and ubiquitin-like modifiers. BMB Rep 2008, 41:435-443. 18593526
62. Calin GA Croce CM MicroRNA signatures in human cancers. Nat Rev Cancer 2006, 6:857-866. 10.1038/nrc1997 17060945
63. Calin GA Croce CM MicroRNA-cancer connection: The beginning of a new tale. Cancer Res 2006, 66:7390-7394. 10.1158/0008-5472.CAN-06-0800 16885332
64. Hoeller D Hecker CM Dikic I Ubiquitin and ubiquitin-like proteins in cancer pathogenesis. Nat Rev Cancer 2006, 6:776-788. 10.1038/nrc1994 16990855
65. Bushati N Cohen SM MicroRNAs in neurodegeneration. Curr Opin Neurobiol 2008, 18:292-296. 10.1016/j.conb.2008.07.001 18662781
66. Rubinsztein DC The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 2006, 443:780-786. 10.1038/nature05291 17051204
67. Scalbert E Bril A Implication of microRNAs in the cardiovascular system. Curr Opin Pharmacol 2008, 8:181-188. 10.1016/j.coph.2007.12.013 18243792
68. Patterson C Ike C Willis PW 4th Stouffer GA Willis MS The bitter end: the ubiquitin-proteasome system and cardiac dysfunction. Circulation 2007, 115:1456-1463. 10.1161/CIRCULATIONAHA.106.649863 17372187
69. Mearini G Schlossarek S Willis MS Carrier L The ubiquitin-proteasome system in cardiac dysfunction. Biochim Biophys Acta 2008, 1782:749-763. 18634872
70. Lenburg ME Liou LS Gerry NP Frampton GM Cohen HT Christman MF Previously unidentified changes in renal cell carcinoma gene expression identified by parametric analysis of microarray data. BMC Cancer 2003, 3:31. 317310 14641932 10.1186/1471-2407-3-31
71. Su AI Wiltshire T Batalov S Lapp H Ching KA Block D Zhang J Soden R Hayakawa M Kreiman G Cooke MP Walker JR Hogenesch JB A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci USA 2004, 101:6062-6067. 395923 15075390 10.1073/pnas.0400782101
72. Ge X Yamamoto S Tsutsumi S Midorikawa Y Ihara S Wang SM Aburatani H Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005, 86:127-141. 10.1016/j.ygeno.2005.04.008 15950434
73. Cordero F Botta M Calogero RA Microarray data analysis and mining approaches. Brief Funct Genomic Proteomic 2007, 6:265-281. 10.1093/bfgp/ elm034 18216026
74. Kilpinen S Autio R Ojala K Iljin K Bucher E Sara H Pisto T Saarela M Skotheim RI Björkman M Mpindi JP Haapa-Paananen S Vainio P Edgren H Wolf M Astola J Nees M Hautaniemi S Kallioniemi O Systematic bioinformatic analysis of expression levels of 17,330 human genes across 9,783 samples from 175 types of healthy and pathological tissues. Genome Biol 2008, 9:R139. 2592717 18803840 10.1186/gb-2008-9-9-r139
75. Yen HC Xu Q Chou DM Zhao Z Elledge SJ Global protein stability profiling in mammalian cells. Science 2008, 322:918-923. 10.1126/science.1160489 18988847
76. Romero P Obradovic Z Li X Garner EC Brown CJ Dunker AK Sequence complexity of disordered protein. Proteins 2001, 42:38-48. 10.1002/ 1097-0134(20010101)42:1<38::AID-PROT50>3.0.CO;2-3 11093259
77. Vucetic S Brown CJ Dunker AK Obradovic Z Flavors of protein disorder. Proteins 2003, 52:573-584. 10.1002/prot.10437 12910457
78. Paliy O Gargac SM Cheng Y Uversky VN Dunker AK Protein disorder is positively correlated with gene expression in Escherichia coli. J Proteome Res 2008, 7:2234-2245. 10.1021/pr800055r 18465893
79. Dunker K Silman I Uversky VN Sussman JL Function and structure of inherantly disordered proteins. Curr Opin Struct Biol 2008, 18:756-764. 10.1016/j.sbi.2008.10.002 18952168
80. Mogka A Schmidta R Bukaua B The N-end rule pathway for regulated proteolysis: Prokaryotic and eukaryotic strategies. Trends Cell Biol 2007, 17:165-172. 10.1016/j.tcb.2007.02.001 17306546
81. Gsponer J Futschik ME Teichmann SA Babu MM Tight regulation of unstructured proteins: From transcript synthesis to protein degradation. Science 2008, 322:1365-1368. 10.1126/science.1163581 19039133
82. Uversky VN Dunker AK Biochemistry: Controlled chaos. Science 2008, 322:1340-1341. 10.1126/science.1167453 19039128
83. Chen J Liang H Fernández A Protein structure protection commits gene expression patterns. Genome Biol 2008, 9:R107. 2530859 18606003 10.1186/gb-2008-9-7-r107
84. Cui Q Yu Z Pan Y Purisima EO Wang E MicroRNAs preferentially target the genes with high transcriptional regulation complexity. Biochem Biophys Res Commun 2007, 352:733-738. 10.1016/j.bbrc.2006.11.080 17141185
85. Cui Q Yu Z Purisima EO Wang E Principles of microRNA regulation of a human cellular signaling network. Mol Syst Biol 2006, 2:46. 1681519 16969338 10.1038/msb4100089
86. Liang H Li WH MicroRNA regulation of human protein protein interaction network. RNA 2007, 13:1402-1408. 1950750 17652130 10.1261/rna.634607
87. Mukhopadhyay D Riezman H Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science 2007, 315:201-205. 10.1126/ science.1127085 17218518
88. Mellman I Nelson WJ Coordinated protein sorting, targeting and distribution in polarized cells. Nat Rev Mol Cell Biol 2008, 9:833-845. 10.1038/nrm2525 18946473
89. Hicke L Dunn R Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins. Annu Rev Cell Dev Biol 2003, 19:141-172. 10.1146/annurev.cellbio.19.110701.154617 14570567
90. Nijman SM Luna-Vargas MP Velds A Brummelkamp TR Dirac AM Sixma TK Bernards R A genomic and functional inventory of deubiquitinating enzymes. Cell 2005, 123:773-786. 10.1016/j.cell.2005.11.007 16325574
91. Ge H Liu Z Church GM Vidal M Correlation between transcriptome and interactome mapping data from Saccharomyces cerevisiae. Nat Genet 2001, 29:482-486. 10.1038/ng776 11694880
92. Jansen R Greenbaum D Gerstein M Relating whole-genome expression data with protein-protein interactions. Genome Res 2002, 12:37-46. 155252 11779829 10.1101/gr.205602
93. Hegyi H Tompa P Intrinsically disordered proteins display no preference for chaperone binding in vivo. PLoS Comput Biol 2008, 4:e1000017. 2265518 18369417 10.1371/journal.pcbi.1000017
94. Kovacs D Rakacs M Agoston B Lenkey K Semrad K Schroeder R Tompa P Janus chaperones: Assistance of both RNA- and protein-folding by ribosomal proteins. FEBS Lett 2008, 583:88-92. 10.1016/j.febslet.2008.11.049 19071121
95. Fuxreiter M Tompa P Simon I Uversky VN Hansen JC Asturias FJ Malleable machines take shape in eukaryotic transcriptional regulation. Nat Chem Biol 2008, 4:728-737. 10.1038/nchembio.127 19008886
96. Tompa P Fuxreiter M Fuzzy complexes: Polymorphism and structural disorder in protein-protein interactions. Trends Biochem Sci 2008, 33:2-8. 10.1016/j.tibs.2007.10.003 18054235
97. Dice JF Chaperone-mediated autophagy. Autophagy 2007, 3:295-299. 17404494
98. Ward JJ McGuffin LJ Bryson K Buxton BF Jones DT The DISOPRED server for the prediction of protein disorder. Bioinformatics 2004, 20:2138-2139. 10.1093/bioinformatics/bth195 15044227
99. Jones DT Improving the accuracy of transmembrane protein topology prediction using evolutionary information. Bioinformatics 2007, 23:538-544. 10.1093/bioinformatics/btl677 17237066
100. Jones DT Taylor WR Thornton JM A model recognition approach to the prediction of all-helical membrane protein structure and topology. Biochemistry 1994, 33:3038-3049. 10.1021/bi00176a037 8130217
101. Barrett T Troup DB Wilhite SE Ledoux P Rudnev D Evangelista C Kim IF Soboleva A Tomashevsky M Edgar R NCBI GEO: Mining tens of millions of expression profiles - database and tools update. Nucleic Acids Res 2007, 35:D760-D765. 1669752 17099226 10.1093/nar/gkl887
102. Wu Z Irizarry RA Preprocessing of oligonucleotide array data. Nat Biotechnol 2004, 22:656-658. 10.1038/nbt0604-656b 15175677
103. Dai M Wang P Boyd AD Kostov G Athey B Jones EG Bunney WE Myers RM Speed TP Akil H Watson SJ Meng F Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data. Nucleic Acids Res 2005, 33:e175. 1283542 16284200 10.1093/nar/gni179
104. Gentleman RC Carey VJ Bates DM Bolstad B Dettling M Dudoit S Ellis B Gautier L Ge Y Gentry J Hornik K Hothorn T Huber W Iacus S Irizarry R Leisch F Li C Maechler M Rossini AJ Sawitzki G Smith C Smyth G Tierney L Yang JY Zhang J Bioconductor: Open software development for computational biology and bioinformatics. Genome Biol 2004, 5:R80. 545600 15461798 10.1186/gb-2004-5-10-r80
105. Sample R code for microarray pre-processing. http://bioinf.cs.ucl.ac.uk/ disorder_regulation/
106. Kasprzyk A Keefe D Smedley D London D Spooner W Melsopp C Hammond M Rocca-Serra P Cox T Birney E EnsMart: A generic system for fast and flexible access to biological data. Genome Res 2004, 14:160-169. 314293 14707178 10.1101/gr.1645104
107. Bruford EA Lush MJ Wright MW Sneddon TP Povey S Birney E The HGNC Database in 2008: A resource for the human genome. Nucleic Acids Res 2008, 36:D445-D448. 2238870 17984084 10.1093/nar/gkm881
108. Flicek P Aken BL Beal K Ballester B Caccamo M Chen Y Clarke L Coates G Cunningham F Cutts T Down T Dyer SC Eyre T Fitzgerald S Fernandez-Banet J Gräf S Haider S Hammond M Holland R Howe KL Howe K Johnson N Jenkinson A Kähäri A Keefe D Kokocinski F Kulesha E Lawson D Longden I Megy K et al Ensembl 2008. Nucleic Acids Res 2008, 36:D707-D714. 2238821 18000006 10.1093/nar/gkm988
109. R: A Language and Environment for Statistical Computing. http://www.R-project.org
110. Farriol-Mathis N Garavelli JS Boeckmann B Duvaud S Gasteiger E Gateau A Veuthey AL Bairoch A Annotation of post-translational modifications in the Swiss-Prot knowledge base. Proteomics 2004, 4:1537-1550. 10.1002/ pmic.200300764 15174124
111. Tung CW Ho SY Computational identification of ubiquitylation sites from protein sequences. BMC Bioinformatics 2008, 9:31. 2267706 18211675 10.1186/1471-2105-9-310
112. Mason SJ Graham NE Areas beneath the relative operating characteristics (ROC) and levels (ROL) curves: Statistical significance and interpretation. Quart J R Meteorol Soc 2002, 128:2145-2166. 10.1256/ 003590002320603584
113. Yen HC Elledge SJ Identification of SCF ubiquitin ligase substrates by global protein stability profiling. Science 2008, 322:923-929. 10.1126/ science.1160462 18988848