| Structural highlights
Disease
[FANCL_HUMAN] Fanconi anemia. The disease is caused by mutations affecting the gene represented in this entry.
Function
[UBE2T_HUMAN] Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. Catalyzes monoubiquitination. Involved in mitomycin-C (MMC)-induced DNA repair: acts as a specific E2 ubiquitin-conjugating enzyme for the Fanconi anemia complex by associating with E3 ubiquitin-protein ligase FANCL and catalyzing monoubiquitination of FANCD2, a key step in the DNA damage pathway. Also mediates monoubiquitination of FANCL and FANCI. May contribute to ubiquitination and degradation of BRCA1. In vitro able to promote polyubiquitination using all 7 ubiquitin Lys residues, but may prefer 'Lys-11'-, 'Lys-27'-, 'Lys-48'- and 'Lys-63'-linked polyubiquitination.[1] [2] [3] [4] [5] [6] [FANCL_HUMAN] Ubiquitin ligase protein that mediates monoubiquitination of FANCD2, a key step in the DNA damage pathway. Also mediates monoubiquitination of FANCI. May stimulate the ubiquitin release from UBE2W. May be required for proper primordial germ cell proliferation in the embryonic stage, whereas it is probably not needed for spermatogonial proliferation after birth.[7] [8] [9] [10] [11]
Publication Abstract from PubMed
The combination of an E2 ubiquitin-conjugating enzyme with an E3 ubiquitin-ligase is essential for ubiquitin modification of a substrate. Moreover, the pairing dictates both the substrate choice and the modification type. The molecular details of generic E3-E2 interactions are well established. Nevertheless, the determinants of selective, specific E3-E2 recognition are not understood. There are approximately 40 E2s and approximately 600 E3s giving rise to a possible approximately 24,000 E3-E2 pairs. Using the Fanconi Anemia pathway exclusive E3-E2 pair, FANCL-Ube2T, we report the atomic structure of the FANCL RING-Ube2T complex, revealing a specific and extensive network of additional electrostatic and hydrophobic interactions. Furthermore, we show that these specific interactions are required for selection of Ube2T over other E2s by FANCL.
Structure of the Human FANCL RING-Ube2T Complex Reveals Determinants of Cognate E3-E2 Selection.,Hodson C, Purkiss A, Miles JA, Walden H Structure. 2013 Dec 31. pii: S0969-2126(13)00466-8. doi:, 10.1016/j.str.2013.12.004. PMID:24389026[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ Alpi A, Langevin F, Mosedale G, Machida YJ, Dutta A, Patel KJ. UBE2T, the Fanconi anemia core complex, and FANCD2 are recruited independently to chromatin: a basis for the regulation of FANCD2 monoubiquitination. Mol Cell Biol. 2007 Dec;27(24):8421-30. Epub 2007 Oct 15. PMID:17938197 doi:http://dx.doi.org/10.1128/MCB.00504-07
- ↑ Alpi AF, Pace PE, Babu MM, Patel KJ. Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI. Mol Cell. 2008 Dec 26;32(6):767-77. doi: 10.1016/j.molcel.2008.12.003. PMID:19111657 doi:http://dx.doi.org/10.1016/j.molcel.2008.12.003
- ↑ Ueki T, Park JH, Nishidate T, Kijima K, Hirata K, Nakamura Y, Katagiri T. Ubiquitination and downregulation of BRCA1 by ubiquitin-conjugating enzyme E2T overexpression in human breast cancer cells. Cancer Res. 2009 Nov 15;69(22):8752-60. doi: 10.1158/0008-5472.CAN-09-1809. Epub , 2009 Nov 3. PMID:19887602 doi:http://dx.doi.org/10.1158/0008-5472.CAN-09-1809
- ↑ Longerich S, San Filippo J, Liu D, Sung P. FANCI binds branched DNA and is monoubiquitinated by UBE2T-FANCL. J Biol Chem. 2009 Aug 28;284(35):23182-6. doi: 10.1074/jbc.C109.038075. Epub 2009, Jul 8. PMID:19589784 doi:http://dx.doi.org/10.1074/jbc.C109.038075
- ↑ David Y, Ziv T, Admon A, Navon A. The E2 ubiquitin conjugating enzymes direct polyubiquitination to preferred lysines. J Biol Chem. 2010 Jan 8. PMID:20061386 doi:M109.089003
- ↑ Meetei AR, de Winter JP, Medhurst AL, Wallisch M, Waisfisz Q, van de Vrugt HJ, Oostra AB, Yan Z, Ling C, Bishop CE, Hoatlin ME, Joenje H, Wang W. A novel ubiquitin ligase is deficient in Fanconi anemia. Nat Genet. 2003 Oct;35(2):165-70. Epub 2003 Sep 14. PMID:12973351 doi:http://dx.doi.org/10.1038/ng1241
- ↑ 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
- ↑ Alpi A, Langevin F, Mosedale G, Machida YJ, Dutta A, Patel KJ. UBE2T, the Fanconi anemia core complex, and FANCD2 are recruited independently to chromatin: a basis for the regulation of FANCD2 monoubiquitination. Mol Cell Biol. 2007 Dec;27(24):8421-30. Epub 2007 Oct 15. PMID:17938197 doi:http://dx.doi.org/10.1128/MCB.00504-07
- ↑ Alpi AF, Pace PE, Babu MM, Patel KJ. Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI. Mol Cell. 2008 Dec 26;32(6):767-77. doi: 10.1016/j.molcel.2008.12.003. PMID:19111657 doi:http://dx.doi.org/10.1016/j.molcel.2008.12.003
- ↑ Longerich S, San Filippo J, Liu D, Sung P. FANCI binds branched DNA and is monoubiquitinated by UBE2T-FANCL. J Biol Chem. 2009 Aug 28;284(35):23182-6. doi: 10.1074/jbc.C109.038075. Epub 2009, Jul 8. PMID:19589784 doi:http://dx.doi.org/10.1074/jbc.C109.038075
- ↑ Hodson C, Purkiss A, Miles JA, Walden H. Structure of the Human FANCL RING-Ube2T Complex Reveals Determinants of Cognate E3-E2 Selection. Structure. 2013 Dec 31. pii: S0969-2126(13)00466-8. doi:, 10.1016/j.str.2013.12.004. PMID:24389026 doi:http://dx.doi.org/10.1016/j.str.2013.12.004
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