Ubiquitin conjugating enzyme

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Function

Ubiquitin conjugating enzyme (Ubc) or E2 enzyme catalyzes the second step in the ubiquitination of a protein tagged to be degraded by the proteasome. Ubiquitin activating enzyme (E1) and ATP produce a C-terminal acyl adenylated ubiquitin molecule which binds to ubiquitin conjugating enzyme (E2) (Ubc) cysteine[1]. The Ubc then binds to ubiquitin ligase (E3) via a conserved binding region. E3 catalyzes the transfer of ubiquitin from the Ubc-ubiquitin complex to a lysine residue of the target protein. Ubc13 makes a catalytically active heterodimer with MMS2[2].

  • UBC2 is required for silencing in yeast[3].
  • UBC4 UBC5 mediate selective degradation of short-lived and abnormal proteins[4].
  • UBC6 and UBC J2 participate in ER-associated protein degradation[5].
  • UBC7 or UBC13 is key in the process of tagging target proteins with Lys63-linked polyubiquitin[6].
    For more details on Ubc13 see UBC13 MMS2.
  • UBC8 is interferon-inducible[7].
  • UBC9 or SUMO conjugating enzyme Ubc9 is required for sumoylation[8].
    For more details on Ubc9 see SUMO conjugating enzyme Ubc9.
  • UBC16 conjugates ubiquitin to its N-terminus and to that of the small ubiquitin-like modifier SUMO[9].
  • UBC D2,D3,Q1 functions in the ubiquitination of the tumor suppressor p53[10].
  • UBC G2 functions in identification and degradation of misfolded proteins in the endoplasmic reticulum.
  • UBC H acts on histones and cytoskeletal proteins[11].
  • UBC K,R1 preferentially catalyses the formation of ubiquitin chain links to proteasome-bound proteins to Lys48[12].
  • UBC S preferentially catalyses the formation of ubiquitin chain links of Lys11 to histones [13].
  • UBC T acts in the Fanconi anemia pathway which is required for the efficient repair of damaged DNA[14].
  • UBC Z is required for FAT10 conjugation (post-translational modification analogous to ubiquitination)[15].
  • UBC Hip-2 mediates amyloid-β neurotoxicity[16].
  • UBC Uev-1 is a variant of UBC which lacks its enzymatic activity[17].

Disease

UBC13 is required for metastatic spread and lung colonizationin breast cancer[18].

Structural highlights

The active site of Ubc contains a cysteine residue. The [19].

3D structures of ubiquitin conjugating enzyme

Structure of human ubiquitin conjugating enzyme E2 (green) complex with ubiquitin (deepskyblue) (PDB entry 3ptf)

Drag the structure with the mouse to rotate

ReferencesReferences

  1. ↑ Markson G, Kiel C, Hyde R, Brown S, Charalabous P, Bremm A, Semple J, Woodsmith J, Duley S, Salehi-Ashtiani K, Vidal M, Komander D, Serrano L, Lehner P, Sanderson CM. Analysis of the human E2 ubiquitin conjugating enzyme protein interaction network. Genome Res. 2009 Oct;19(10):1905-11. Epub 2009 Jun 23. PMID:19549727 doi:http://dx.doi.org/gr.093963.109
  2. ↑ Eddins MJ, Carlile CM, Gomez KM, Pickart CM, Wolberger C. Mms2-Ubc13 covalently bound to ubiquitin reveals the structural basis of linkage-specific polyubiquitin chain formation. Nat Struct Mol Biol. 2006 Oct;13(10):915-20. Epub 2006 Sep 17. PMID:16980971 doi:10.1038/nsmb1148
  3. ↑ Huang H, Kahana A, Gottschling DE, Prakash L, Liebman SW. The ubiquitin-conjugating enzyme Rad6 (Ubc2) is required for silencing in Saccharomyces cerevisiae. Mol Cell Biol. 1997 Nov;17(11):6693-9. PMID:9343433
  4. ↑ Seufert W, Jentsch S. Ubiquitin-conjugating enzymes UBC4 and UBC5 mediate selective degradation of short-lived and abnormal proteins. EMBO J. 1990 Feb;9(2):543-50. PMID:2154373
  5. ↑ Lenk U, Yu H, Walter J, Gelman MS, Hartmann E, Kopito RR, Sommer T. A role for mammalian Ubc6 homologues in ER-associated protein degradation. J Cell Sci. 2002 Jul 15;115(Pt 14):3007-14. PMID:12082160
  6. ↑ Yamamoto M, Okamoto T, Takeda K, Sato S, Sanjo H, Uematsu S, Saitoh T, Yamamoto N, Sakurai H, Ishii KJ, Yamaoka S, Kawai T, Matsuura Y, Takeuchi O, Akira S. Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling. Nat Immunol. 2006 Sep;7(9):962-70. doi: 10.1038/ni1367. Epub 2006 Jul 23. PMID:16862162 doi:http://dx.doi.org/10.1038/ni1367
  7. ↑ Kim KI, Giannakopoulos NV, Virgin HW, Zhang DE. Interferon-inducible ubiquitin E2, Ubc8, is a conjugating enzyme for protein ISGylation. Mol Cell Biol. 2004 Nov;24(21):9592-600. doi: 10.1128/MCB.24.21.9592-9600.2004. PMID:15485925 doi:http://dx.doi.org/10.1128/MCB.24.21.9592-9600.2004
  8. ↑ Tahmasebi S, Ghorbani M, Savage P, Gocevski G, Yang XJ. The SUMO conjugating enzyme Ubc9 is required for inducing and maintaining stem cell pluripotency. Stem Cells. 2014 Apr;32(4):1012-20. doi: 10.1002/stem.1600. PMID:24706591 doi:http://dx.doi.org/10.1002/stem.1600
  9. ↑ Tatham MH, Plechanovova A, Jaffray EG, Salmen H, Hay RT. Ube2W conjugates ubiquitin to alpha-amino groups of protein N-termini. Biochem J. 2013 Jul 1;453(1):137-45. doi: 10.1042/BJ20130244. PMID:23560854 doi:http://dx.doi.org/10.1042/BJ20130244
  10. ↑ Shafiee SM, Rasti M, Seghatoleslam A, Azimi T, Owji AA. UBE2Q1 in a Human Breast Carcinoma Cell Line: Overexpression and Interaction with p53. Asian Pac J Cancer Prev. 2015;16(9):3723-7. PMID:25987028
  11. ↑ Martin I, Vourc'h P, Mahe M, Thepault RA, Antar C, Vedrine S, Praline J, Camu W, Andres CR, Corcia P. Association study of the ubiquitin conjugating enzyme gene UBE2H in sporadic ALS. Amyotroph Lateral Scler. 2009 Oct-Dec;10(5-6):432-5. doi:, 10.3109/17482960802444972. PMID:19922136 doi:http://dx.doi.org/10.3109/17482960802444972
  12. ↑ Middleton AJ, Day CL. The molecular basis of lysine 48 ubiquitin chain synthesis by Ube2K. Sci Rep. 2015 Nov 23;5:16793. doi: 10.1038/srep16793. PMID:26592444 doi:http://dx.doi.org/10.1038/srep16793
  13. ↑ Paul A, Wang B. RNF8- and Ube2S-Dependent Ubiquitin Lysine 11-Linkage Modification in Response to DNA Damage. Mol Cell. 2017 May 18;66(4):458-472.e5. doi: 10.1016/j.molcel.2017.04.013. PMID:28525740 doi:http://dx.doi.org/10.1016/j.molcel.2017.04.013
  14. ↑ Machida YJ, Machida Y, Chen Y, Gurtan AM, Kupfer GM, D'Andrea AD, Dutta A. UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation. Mol Cell. 2006 Aug;23(4):589-96. PMID:16916645 doi:http://dx.doi.org/10.1016/j.molcel.2006.06.024
  15. ↑ Schelpe J, Monte D, Dewitte F, Sixma TK, Rucktooa P. Structure of UBE2Z provides functional insight into specificity in the FAT10 conjugation machinery. J Biol Chem. 2015 Nov 10. pii: jbc.M115.671545. PMID:26555268 doi:http://dx.doi.org/10.1074/jbc.M115.671545
  16. ↑ Song S, Kim SY, Hong YM, Jo DG, Lee JY, Shim SM, Chung CW, Seo SJ, Yoo YJ, Koh JY, Lee MC, Yates AJ, Ichijo H, Jung YK. Essential role of E2-25K/Hip-2 in mediating amyloid-beta neurotoxicity. Mol Cell. 2003 Sep;12(3):553-63. PMID:14527403
  17. ↑ Sancho E, Vila MR, Sanchez-Pulido L, Lozano JJ, Paciucci R, Nadal M, Fox M, Harvey C, Bercovich B, Loukili N, Ciechanover A, Lin SL, Sanz F, Estivill X, Valencia A, Thomson TM. Role of UEV-1, an inactive variant of the E2 ubiquitin-conjugating enzymes, in in vitro differentiation and cell cycle behavior of HT-29-M6 intestinal mucosecretory cells. Mol Cell Biol. 1998 Jan;18(1):576-89. PMID:9418904
  18. ↑ Wu X, Zhang W, Font-Burgada J, Palmer T, Hamil AS, Biswas SK, Poidinger M, Borcherding N, Xie Q, Ellies LG, Lytle NK, Wu LW, Fox RG, Yang J, Dowdy SF, Reya T, Karin M. Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade. Proc Natl Acad Sci U S A. 2014 Sep 23;111(38):13870-5. doi:, 10.1073/pnas.1414358111. Epub 2014 Sep 4. PMID:25189770 doi:http://dx.doi.org/10.1073/pnas.1414358111
  19. ↑ Bosanac I, Phu L, Pan B, Zilberleyb I, Maurer B, Dixit VM, Hymowitz SG, Kirkpatrick DS. Modulation of K11-Linkage Formation by Variable Loop Residues within UbcH5A. J Mol Biol. 2011 May 6;408(3):420-31. Epub 2011 Mar 10. PMID:21396940 doi:10.1016/j.jmb.2011.03.011

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