泛素连接酶-底物选择关系的研究进展

doi:10.13560/j.cnki.biotech.bull.1985.2015.01.002

摘要/Abstract

摘要： 泛素是一种包含76个氨基酸的小分子蛋白。泛素共价结合到底物的过程称为泛素化修饰。泛素化修饰过程是一个由级联的泛素激活酶、泛素结合酶和泛素连接酶所介导的复杂过程，泛素化修饰具有高效、ATP依赖、高度特异的特点。泛素化修饰与细胞周期调控、细胞凋亡、转录调控、DNA损伤修复等一系列生物学过程密切相关。在泛素化修饰过程中，泛素连接酶对底物的识别，是决定泛素化修饰特异性的关键环节。泛素连接酶底物识别的相关机制研究不断被报道，鉴定泛素连接酶底物的高通量方法也在不断的改进和发展。随着实验研究的不断深入，实验数据的不断产出，利用生物信息学进行泛素连接酶底物的研究也开始受到关注。对泛素连接酶识别底物的相关机制、高通量泛素连接酶底物的鉴定方法、泛素连接酶底物的生物信息学研究和生物信息学在泛素连接酶底物研究中的发展方向进行讨论。

关键词: 泛素化修饰, 泛素连接酶, 底物, 生物信息学

Abstract: Ubiquitin is a small-molecule protein composed of 76 amino acids. The covalent-bonding process between ubiquitin and substrates is defined as Ubiquitination. Ubiquitination modification, an efficient, ATP-dependent, and highly specific process, is mediated by a cascade regulation of ubiquitin activating enzymes, ubiquitin conjugating enzymes, ubiquitin ligase and deubiquitinating enzymes. Ubiquitination is highly relevant with biological processes like cell cycle regulation, cell apoptosis, transcription regulation, DNA damage response and so on. In the process of ubiquitination, the recognition between ubiquitin ligases and substrates is critical for the specificity. The mechanisms of such recognition are being reported moreover the high throughput methods identifying E3’s substrate are being improved and developed. With the accumulation of ubiquitination data from the deep-going research, the bioinformatics approach studying the selective relationship between E3s and substrates is becoming a hot spot. This article will discuss the recognition mechanism between E3s and substrates, the high throughput methods used for the identification of E3’s substrates, review the bioinformatics study about E3s’ substrates and highlight the future research direction.

Key words: ubiquitination, ubiquitin-ligase, substrate, bioinformatics

李杨,李栋. 泛素连接酶-底物选择关系的研究进展[J]. 生物技术通报, 2015, 31(1): 11-20.

Li Yang, Li Dong. Research Advances in the Selective Relationship Between Ubiquitin Ligases and Substrates[J]. Biotechnology Bulletin, 2015, 31(1): 11-20.

参考文献

[1] Goldstein G, Scheid M, Hammerling U, et al. Isolation of a polypep-tide that has lymphocyte-differentiating properties and is probably represented universally in living cells[J]. Proceedings of the National Academy of Sciences, 1975, 72（1）：11-15.
[2] Pickart CM, Eddins MJ. Ubiquitin：structures, functions, mechanis-ms[J]. Biochimica et Biophysica Acta（BBA）-Molecular Cell Research, 2004, 1695（1-3）：55-72.
[3] Komander D, Rape M. The ubiquitin code[J]. Annual Review of Biochemistry, 2012, 81：203-229.
[4] Komander D. The emerging complexity of protein ubiquitination[J]. Biochemical Society Transactions, 2009, 37（Pt 5）：937-953.
[5] Miranda M, Sorkin A. Regulation of receptors and transporters by ubiquitination：new insights into surprisingly similar mechanis-ms[J]. Molecular Interventions, 2007, 7（3）：157-167.
[6] Ikeda F, Dikic I. Atypical ubiquitin chains：new molecular signals[J]. EMBO Reports, 2008, 9（6）：536-542.
[7] Ciechanover A, Ben-Saadon R. N-terminal ubiquitination：more protein substrates join in[J]. Trends in Cell Biol, 2004, 14：103-106.
[8] Deshaies RJ, Joazeiro CAP. RING domain E3 ubiquitin ligases[J]. Annual Review of Biochemistry, 2009, 78：399-434.
[9] Michelle C, Vourc’h P, Mignon L, et al. What was the set of ubiqui-tin and ubiquitin-like conjugating enzymes in the eukaryote common ancestor?[J]. J Mol Evol, 2009, 68（6）：616-628.
[10] Moynagh PN. The roles of Pellino E3 ubiquitin ligases in immuni-ty[J]. Nature Reviews Immunology, 2014, 14（2）：122-131.
[11] Wrighton KH. DNA damage response：a ligase makes sense of DNA damage[J]. Nature Reviews Molecular Cell Biology, 2014, 15（2）：76-77.
[12] Guo X, Baillo A, Dutta SM, et al. HTLV-1 Tax binds to and stabilizes the SUMO-targeted ubiquitin ligase RNF4 during DNA damage response[J]. Retrovirology, 2014, 11（Suppl 1）：98.
[13] Zhang S, Zhou Y, Sarkeshik A, et al. Identification of RNF8 as a ubiquitin ligase involved in targeting the p12 subunit of DNA polymerase δ for degradation in response to DNA damage[J]. Journal of Biological Chemistry, 2014, 288（5）：2941-2950.
[14] Inuzuka H, Shaik S, Onoyama I, et al. SCFFBW7 regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction[J]. Nature, 2011, 471（7336）：104-109.
[15] Santra MK, Wajapeyee N, Green MR. F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage[J]. Nature, 2009, 459（7247）：722-725.
[16] Paolino M, Choidas A, Wallner S, et al. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells[J]. Nature, 2014, 507（7493）：508-512.
[17] Duan S, Cermak L, Pagan JK, et al. FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas[J]. Nature, 2012, 481（7379）：90-93.
[18] Severe N, Dieudonné FX, Marie PJ. E3 ubiquitin ligase-mediated regulation of bone formation and tumorigenesis[J]. Cell Death & Disease, 2013, 4（1）：e463.
[19] Berkers CR, Ovaa H. Drug discovery and assay development in the ubiquitinproteasome system[J]. Biochemical Society Transactions, 2010, 38（1）：14.
[20] Yang Y, Ludwig RL, Jensen JP, et al. Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53in cells[J]. Cancer Cell, 2005, 7（6）：547-559.
[21] Obenauer JC, Cantley LC, Yaffe MB. Scansite 2.0：proteome-wide prediction of cell signaling interactions using short sequence motifs[J]. Nucleic Acids Res, 2003, 31（13）：3635-3641.
[22] Lindon C, Pines J. Ordered proteolysis in anaphase inactivates Plk1 to contribute to proper mitotic exit in human cells[J]. The Journal of Cell Biology, 2004, 164（2）：233-241.
[23] Lasorella A, Stegmüller J, Guardavaccaro D, et al. Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth[J]. Nature, 2006, 442（7101）：471-474.
[24] Pfleger CM, Kirschner MW. The KEN box：an APC recognition signal distinct from the D box targeted by Cdh1[J]. Genes & Development, 2000, 14（6）：655-665.
[25] Arquint C, Nigg EA. STIL Microcephaly mutations interfere with APC/C-mediated degradation and cause centriole amplification[J]. Current Biology, 2014, 24（4）：351-360.
[26] Ichim G, Mola M, Finkbeiner MG, et al. The histone acetyltransferase component TRRAP is targeted for destruction during the cell cycle[J]. Oncogene, 2014, 33（2）：181-192.
[27] Ingham RJ, Gish G, Pawson T. The Nedd4 family of E3 ubiquitin ligases：functional diversity within a common modular architecture[J]. Oncogene, 2004, 23（11）：1972-1984.
[28] Rotin D, Kumar S. Physiological functions of the HECT family of ubiquitin ligases[J]. Nature Reviews Molecular Cell Biology, 2009, 10（6）：398-409.
[29] Graham L, Padmanabhan S. NEDD4L in essential hypertension[J]. Journal of Hypertension, 2014, 32（2）：230-232.
[30] Fei C, He X, Xie S, et al. Smurf1-mediated axin ubiquitination requires Smurf1 C2 domain and is cell-cycle dependent[J]. Journal of Biological Chemistry, 2014, 289（20）：14170-14177.
[31] Zhi X, Chen C. WWP1：a versatile ubiquitin E3 ligase in signaling and diseases[J]. Cell Mol Life Sci, 2012, 69（9）：1425-1434.
[32] Kavsak P, Rasmussen RK, Causing CG, et al. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGFβ receptor for degradation[J]. Molecular Cell, 2000, 6（6）：1365-1375.
[33] Geetha T, Jiang J, Wooten MW. Lysine 63 polyubiquitination of the nerve growth factor receptor TrkA directs internalization and signaling[J]. Molecular Cell, 2005, 20（2）：301-312.
[34] Laney JD, Hochstrasser M. Substrate targeting in the ubiquitin system[J]. Cell, 1999, 97（4）：427-430.
[35] An H, Krist DT, Statsyuk AV. Crosstalk between kinases and Nedd4 family ubiquitin ligases[J]. Molecular Biosystems, 2014, 10（7）：1643-1657.
[36] Zhao Y, Brickner JR, Majid MC, et al. Crosstalk between ubiquitin and other post-translational modifications on chromatin during double-strand break repair[J]. Trends in Cell Biology, 2014, 24（7）：426-434.
[37] Gill G. SUMO and ubiquitin in the nucleus：different functions, similar mechanisms?[J]. Genes & Development, 2004, 18（17）：2046-2059.
[38] Kawakami T, Chiba T, Suzuki T, et al. NEDD8 recruits E2-ubiquitin to SCF E3 ligase[J]. The EMBO Journal, 2001, 20（15）：4003-4012.
[39] Darwanto A, Curtis MP, Schrag M, et al. A modified “cross-talk” between histone H2B Lys-120 ubiquitination and H3 Lys-79 methylation[J]. J Biol Chem, 2010, 285（28）：21868-21876.
[40] Lee JS, Shukla A, Schneider J, et al. Histone crosstalk between H2B monoubiquitination and H3 methylation mediated by COMPASS[J]. Cell, 2007, 131（6）：1084-1096.
[41] Yen HCS, Xu Q, Chou DM, et al. Global protein stability profiling in mammalian cells[J]. Science, 2008, 322（5903）：918-923.
[42] Yen HCS, Elledge SJ. Identification of SCF ubiquitin ligase substrates by global protein stability profiling[J]. Science, 2008, 322（5903）：923-929.
[43] Andrews PS, Schneider S, Yang E, et al. Identification of substrates of SMURF1 ubiquitin ligase activity utilizing protein microarrays[J]. Assay and Drug Development Technologies, 2010, 8（4）：471-487.
[44] Loch CM, Eddins MJ, Strickler JE. Protein microarrays for the identification of praja1 e3 ubiquitin ligase substrates[J]. Cell Biochemistry and Biophysics, 2011, 60（1-2）：127-135.
[45] Guo Z, Wang X, Li H, et al. Screening E3 substrates using a live phage display library[J]. PloS One, 2013, 8（10）：e76622.
[46] Yumimoto K, Matsumoto M, Oyamada K, et al. Comprehensive identification of substrates for F-box proteins by differential proteomics analysis[J]. Journal of Proteome Research, 2012, 11（6）：3175-3185.
[47] Shi Y, Chan DW, Jung SY, et al. A data set of human endogenous protein ubiquitination sites[J]. Molecular & Cellular Proteomics, 2011, 10（5）：M110. 002089.
[48] Rubel CE, Schisler JC, Hamlett ED, et al. Diggin' on U（biquitin）：a novel method for the identification of physiological E3 ubiquitin ligase sustrates[J]. Cell Biochemistry and Biophysics, 2013, 67（1）：127-138.
[49] Zhuang M, Guan S, Wang H, et al. Substrates of IAP ubiquitin ligases identified with a designed orthogonal E3 ligase, the NEDDylator[J]. Molecular Cell, 2013, 49（2）：273-282.
[50] Han Y, Lee H, Park JC, et al. E3Net：a system for exploring E3-mediated regulatory networks of cellular functions[J]. Molecular & Cellular Proteomics, 2012, 11（4）：0111.
[51] Du Y, Xu N, Lu M, et al. hUbiquitome：a database of experimen-tally verified ubiquitination cascades in humans[J]. Database, 2011, 2011：bar055.
[52] Lee WC, Lee M, Jung JW, et al. SCUD：Saccharomyces cerevisiae ubiquitination database[J]. BMC Genomics, 2008, 9（1）：440.
[53] Chernorudskiy AL, Garcia A, Eremin EV, et al. UbiProt：a database of ubiquitylated proteins[J]. BMC Bioinformatics, 2007, 8（1）：126.
[54] Du Z, Zhou X, Li L, et al. PlantsUPS：a database of plants’ Ubiquitin Proteasome System[J]. BMC Genomics, 2009, 10（1）：227.
[55] Jadhav TS, Wooten MW, Wooten MC. Mining the TRAF6/p62 interactome for a selective ubiquitination motif[J]. BMC Proc, 2011, 5（suppl 2）：S4.
[56] Liu ZX, Yuan F, Ren J, et al. GPS-ARM：computational analysis of the APC/C recognition motif by predicting D-boxes and KEN-boxes[J]. PloS One, 2012, 7（3）：e34370.
[57] Xue Y, Zhou F, Zhu M, et al. GPS：a comprehensive www server for phosphorylation sites prediction[J]. Nucleic Acids Research, 2005, 33（suppl 2）：W184-W187.
[58] Xue Y, Ren J, Gao X, et al. GPS 2.0, a tool to predict kinase-specific phosphorylation sites in hierarchy[J]. Molecular & Cellular Proteomics, 2008, 7（9）：1598-1608.
[59] Jansen R, Yu H, Greenbaum D, et al. A Bayesian networks approach for predicting protein-protein interactions from genomic data[J]. Science, 2003, 302（5644）：449-453.
[60] Rhodes DR, Tomlins SA, Varambally S, et al. Probabilistic model of the human protein-protein interaction network[J]. Nature Biotechnology, 2005, 23（8）：951-959.
[61] Li D, Liu W, Liu Z, et al. PRINCESS, a protein interaction confidence evaluation system with multiple data sources[J]. Molecular & Cellular Proteomics, 2008, 7（6）：1043-1052.
[62] Zhang Q C, Petrey D, Deng L, et al. Structure-based prediction of protein-protein interactions on a genome-wide scale[J]. Nature, 2012, 490（7421）：556-560.
[63] Snel B, Lehmann G, Bork P, et al. STRING：a web-server to retrieve and display the repeatedly occurring neighbourhood of a gene[J]. Nucleic Acids Research, 2000, 28（18）：3442-3444.
[64] Thierry-Mieg N. A new pooling strategy for high-throughput screening：the Shifted Transversal Design[J]. BMC Bioinforma-tics, 2006, 7（1）：28.