Ubiquitin-conjugating enzyme E2 variant 2 is a protein that in humans is encoded by the UBE2V2gene.[1][2] Ubiquitin-conjugating enzyme E2 variant proteins constitute a distinct subfamily within the E2 protein family.
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.[3]
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 polyubituitin 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]
↑Fritsche J, Rehli M, Krause SW, Andreesen R, Kreutz M (June 1997). "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. doi:10.1006/bbrc.1997.6798. PMID9199207.
Gevaert K, Goethals M, Martens L, Van Damme J, Staes A, Thomas GR, Vandekerckhove J (May 2003). "Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides". Nature Biotechnology. 21 (5): 566–9. doi:10.1038/nbt810. PMID12665801.
Bothos J, Summers MK, Venere M, Scolnick DM, Halazonetis TD (October 2003). "The Chfr mitotic checkpoint protein functions with Ubc13-Mms2 to form Lys63-linked polyubiquitin chains". Oncogene. 22 (46): 7101–7. doi:10.1038/sj.onc.1206831. PMID14562038.
Zhou H, Wertz I, O'Rourke K, Ultsch M, Seshagiri S, Eby M, Xiao W, Dixit VM (January 2004). "Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO". Nature. 427 (6970): 167–71. doi:10.1038/nature02273. PMID14695475.
Simpson LJ, Sale JE (April 2005). "UBE2V2 (MMS2) is not required for effective immunoglobulin gene conversion or DNA damage tolerance in DT40". DNA Repair. 4 (4): 503–10. doi:10.1016/j.dnarep.2004.12.002. PMID15725630.
Pastushok L, Moraes TF, Ellison MJ, Xiao W (May 2005). "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. doi:10.1074/jbc.M410469200. PMID15749714.
Spyracopoulos L, Lewis MJ, Saltibus LF (June 2005). "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. doi:10.1021/bi050065k. PMID15952783.
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 (September 2005). "A human protein-protein interaction network: a resource for annotating the proteome". Cell. 122 (6): 957–68. doi:10.1016/j.cell.2005.08.029. PMID16169070.
Wen R, Newton L, Li G, Wang H, Xiao W (May 2006). "Arabidopsis thaliana UBC13: implication of error-free DNA damage tolerance and Lys63-linked polyubiquitylation in plants". Plant Molecular Biology. 61 (1–2): 241–53. doi:10.1007/s11103-006-0007-x. PMID16786304.
Zhao GY, Sonoda E, Barber LJ, Oka H, Murakawa Y, Yamada K, Ikura T, Wang X, Kobayashi M, Yamamoto K, Boulton SJ, Takeda S (March 2007). "A critical role for the ubiquitin-conjugating enzyme Ubc13 in initiating homologous recombination". Molecular Cell. 25 (5): 663–75. doi:10.1016/j.molcel.2007.01.029. PMID17349954.
