UBE2V2 explained

Ubiquitin-conjugating enzyme E2 variant 2 is a protein that in humans is encoded by the UBE2V2 gene.^{[1] [2]} Ubiquitin-conjugating enzyme E2 variant proteins constitute a distinct subfamily within the E2 protein family.

Structure

UBE2V2 has sequence similarity to other ubiquitin-conjugating enzymes but lack the conserved cysteine residue that is critical for the catalytic activity of E2s. The protein encoded by this gene also shares homology with ubiquitin-conjugating enzyme E2 variant 1 and yeast MMS2 gene product.^[3]

Function

UBE2V2 has also been implicated as an intracellular sensor of reactive electrophilic species, which are present in high levels during periods of pathogenic and/or environmental stress.^[4] The C69 residue of UBE2V2 is capable of binding with various RES. It has been shown that binding of RES to UBE2V2 promotes UBE2V2-mediated activation of Ube2N, another E2 protein that complexes with UBE2V2. Activated Ube2N has been shown to play a major role in promoting DNA-damage responses. Thus, UBE2V2 may promote genome integrity by directly sensing RES and effecting DNA damage responses.^[5] It may also be involved in the differentiation of monocytes and enterocytes.

Interactions

UBE2V2 has been shown to interact with HLTF.^[6] Although UBE2V2 itself lacks ubiquitin-conjugating activity, it can interact with different Ubiquitin-conjugating enzymes to facilitate their catalytic activities.^[7] For instance, UBE2V2 can complex with UBE2N to form a heterodimer capable of synthesizing Lys-63 linked polyubiquitin chains.^[8] UBE2V2 may facilitate UBE2N activity by coordinating UBE2N's positioning to promote ubiquitin chain formation specifically at Lys-63, as the ubiquitin molecule has multiple potential Lysine binding sites.^[9] Similarly, it has been shown that UBE2V2 interact with the ubiquitin-conjugating enzyme, Ubc13, to induce Ubc13 to adopt an active conformation that can create Lys-63 polyubiquitin chains on various substrates.^[10]

Addition of Lys-63 polyubiquitin chains to intracellular targets is distinct from the canonical Lys-48 polyubiquitin chains in that Lys-63 chains do not mediate proteasomal degradation of its substrate.^[11] Although their function remains poorly characterized, Lys-63 chains have been shown to regulate signaling pathways by either activating or inhibiting its target protein function.^[12] For example, TRIM5alpha restriction of retroviral reverse-transcription is dependent on UBE2V2/UBE2N-mediated poly-ubiquitination.^[13] UBE2V2 has been shown to regulate TRIM21 antiviral activity in an analogous manner.^[14]

Further reading

• Xiao W, Lin SL, Broomfield S, Chow BL, Wei YF . The products of the yeast MMS2 and two human homologs (hMMS2 and CROC-1) define a structurally and functionally conserved Ubc-like protein family . Nucleic Acids Research . 26 . 17 . 3908–14 . September 1998 . 9705497 . 147796 . 10.1093/nar/26.17.3908 .
• Hofmann RM, Pickart CM . Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair . Cell . 96 . 5 . 645–53 . March 1999 . 10089880 . 10.1016/S0092-8674(00)80575-9 . 17117789 . free .
• Chan NL, Hill CP . Defining polyubiquitin chain topology . Nature Structural Biology . 8 . 8 . 650–2 . August 2001 . 11473244 . 10.1038/90337 . 16579945 .
• Moraes TF, Edwards RA, McKenna S, Pastushok L, Xiao W, Glover JN, Ellison MJ . Crystal structure of the human ubiquitin conjugating enzyme complex, hMms2-hUbc13 . Nature Structural Biology . 8 . 8 . 669–73 . August 2001 . 11473255 . 10.1038/90373 . 23504541 .
• Gevaert K, Goethals M, Martens L, Van Damme J, Staes A, Thomas GR, Vandekerckhove J . Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides . Nature Biotechnology . 21 . 5 . 566–9 . May 2003 . 12665801 . 10.1038/nbt810 . 23783563 .
• Bothos J, Summers MK, Venere M, Scolnick DM, Halazonetis TD . The Chfr mitotic checkpoint protein functions with Ubc13-Mms2 to form Lys63-linked polyubiquitin chains . Oncogene . 22 . 46 . 7101–7 . October 2003 . 14562038 . 10.1038/sj.onc.1206831 . free .
• Zhou H, Wertz I, O'Rourke K, Ultsch M, Seshagiri S, Eby M, Xiao W, Dixit VM . Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO . Nature . 427 . 6970 . 167–71 . January 2004 . 14695475 . 10.1038/nature02273 . 2004Natur.427..167Z . 4429582 .
• Simpson LJ, Sale JE . UBE2V2 (MMS2) is not required for effective immunoglobulin gene conversion or DNA damage tolerance in DT40 . DNA Repair . 4 . 4 . 503–10 . April 2005 . 15725630 . 10.1016/j.dnarep.2004.12.002 .
• Pastushok L, Moraes TF, Ellison MJ, Xiao W . A single Mms2 "key" residue insertion into a Ubc13 pocket determines the interface specificity of a human Lys63 ubiquitin conjugation complex . The Journal of Biological Chemistry . 280 . 18 . 17891–900 . May 2005 . 15749714 . 10.1074/jbc.M410469200 . free .
• Spyracopoulos L, Lewis MJ, Saltibus LF . Main chain and side chain dynamics of the ubiquitin conjugating enzyme variant human Mms2 in the free and ubiquitin-bound States . Biochemistry . 44 . 24 . 8770–81 . June 2005 . 15952783 . 10.1021/bi050065k .
• Andersen PL, Zhou H, Pastushok L, Moraes T, McKenna S, Ziola B, Ellison MJ, Dixit VM, Xiao W . Distinct regulation of Ubc13 functions by the two ubiquitin-conjugating enzyme variants Mms2 and Uev1A . The Journal of Cell Biology . 170 . 5 . 745–55 . August 2005 . 16129784 . 2171356 . 10.1083/jcb.200502113 .
• Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE . A human protein-protein interaction network: a resource for annotating the proteome . Cell . 122 . 6 . 957–68 . September 2005 . 16169070 . 10.1016/j.cell.2005.08.029 . 11858/00-001M-0000-0010-8592-0 . 8235923 . free .
• Wen R, Newton L, Li G, Wang H, Xiao W . Arabidopsis thaliana UBC13: implication of error-free DNA damage tolerance and Lys63-linked polyubiquitylation in plants . Plant Molecular Biology . 61 . 1–2 . 241–53 . May 2006 . 16786304 . 10.1007/s11103-006-0007-x . 8437446 .
• Zhao GY, Sonoda E, Barber LJ, Oka H, Murakawa Y, Yamada K, Ikura T, Wang X, Kobayashi M, Yamamoto K, Boulton SJ, Takeda S . A critical role for the ubiquitin-conjugating enzyme Ubc13 in initiating homologous recombination . Molecular Cell . 25 . 5 . 663–75 . March 2007 . 17349954 . 10.1016/j.molcel.2007.01.029 . free .

Notes and References

1. Sancho E, Vilá MR, Sánchez-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 . Molecular and Cellular Biology . 18 . 1 . 576–89 . January 1998 . 9418904 . 121525 . 10.1128/mcb.18.1.576 .
2. Fritsche J, Rehli M, Krause SW, Andreesen R, Kreutz M . Molecular cloning of a 1alpha,25-dihydroxyvitamin D3-inducible transcript (DDVit 1) in human blood monocytes . Biochemical and Biophysical Research Communications . 235 . 2 . 407–12 . June 1997 . 9199207 . 10.1006/bbrc.1997.6798 .
3. Web site: Entrez Gene: UBE2V2 ubiquitin-conjugating enzyme E2 variant 2.
4. Farmer EE, Davoine C . Reactive electrophile species . Current Opinion in Plant Biology . 10 . 4 . 380–6 . August 2007 . 17646124 . 10.1016/j.pbi.2007.04.019 .
5. Zhao Y, Long MJ, Wang Y, Zhang S, Aye Y . Ube2V2 Is a Rosetta Stone Bridging Redox and Ubiquitin Codes, Coordinating DNA Damage Responses . ACS Central Science . 4 . 2 . 246–259 . February 2018 . 29532025 . 5833000 . 10.1021/acscentsci.7b00556 .
6. Unk I, Hajdú I, Fátyol K, Hurwitz J, Yoon JH, Prakash L, Prakash S, Haracska L . Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination . Proceedings of the National Academy of Sciences of the United States of America . 105 . 10 . 3768–73 . March 2008 . 18316726 . 2268824 . 10.1073/pnas.0800563105 . 2008PNAS..105.3768U . free .
7. Stewart MD, Ritterhoff T, Klevit RE, Brzovic PS . E2 enzymes: more than just middle men . Cell Research . 26 . 4 . 423–40 . April 2016 . 27002219 . 4822130 . 10.1038/cr.2016.35 .
8. Fletcher AJ, Christensen DE, Nelson C, Tan CP, Schaller T, Lehner PJ, Sundquist WI, Towers GJ . TRIM5α requires Ube2W to anchor Lys63-linked ubiquitin chains and restrict reverse transcription . The EMBO Journal . 34 . 15 . 2078–95 . August 2015 . 26101372 . 4551353 . 10.15252/embj.201490361 .
9. 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 . Nature Structural & Molecular Biology . 13 . 10 . 915–20 . October 2006 . 16980971 . 10.1038/nsmb1148 . 6757737 .
10. Branigan E, Plechanovová A, Jaffray EG, Naismith JH, Hay RT . Structural basis for the RING-catalyzed synthesis of K63-linked ubiquitin chains . Nature Structural & Molecular Biology . 22 . 8 . 597–602 . August 2015 . 26148049 . 4529489 . 10.1038/nsmb.3052 .
11. Fletcher AJ, Christensen DE, Nelson C, Tan CP, Schaller T, Lehner PJ, Sundquist WI, Towers GJ . TRIM5α requires Ube2W to anchor Lys63-linked ubiquitin chains and restrict reverse transcription . The EMBO Journal . 34 . 15 . 2078–95 . August 2015 . 26101372 . 4551353 . 10.15252/embj.201490361 .
12. Web site: UBE2N - Ubiquitin-conjugating enzyme E2 N - Homo sapiens (Human) - UBE2N gene & protein. www.uniprot.org. en. 2018-04-06.
13. Fletcher AJ, Christensen DE, Nelson C, Tan CP, Schaller T, Lehner PJ, Sundquist WI, Towers GJ . TRIM5α requires Ube2W to anchor Lys63-linked ubiquitin chains and restrict reverse transcription . The EMBO Journal . 34 . 15 . 2078–95 . August 2015 . 26101372 . 4551353 . 10.15252/embj.201490361 .
14. Fletcher AJ, Mallery DL, Watkinson RE, Dickson CF, James LC . Sequential ubiquitination and deubiquitination enzymes synchronize the dual sensor and effector functions of TRIM21 . Proceedings of the National Academy of Sciences of the United States of America . 112 . 32 . 10014–9 . August 2015 . 26150489 . 4538650 . 10.1073/pnas.1507534112 . 2015PNAS..11210014F . free .