6r75: Difference between revisions

Latest revision as of 12:16, 24 January 2024

Crystal structure of human Ube2T E54R mutant

Structural highlights

6r75 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

DNA-damage repair is implemented by proteins that are coordinated by specialized molecular signals. One such signal in the Fanconi anemia (FA) pathway for the repair of DNA interstrand crosslinks is the site-specific monoubiquitination of FANCD2 and FANCI. The signal is mediated by a multiprotein FA core complex (FA-CC) however, the mechanics for precise ubiquitination remain elusive. We show that FANCL, the RING-bearing module in FA-CC, allosterically activates its cognate ubiqutin-conjugating enzyme E2 UBE2T to drive site-specific FANCD2 ubiquitination. Unlike typical RING E3 ligases, FANCL catalyzes ubiquitination by rewiring the intraresidue network of UBE2T to influence the active site. Consequently, a basic triad unique to UBE2T engages a structured acidic patch near the target lysine on FANCD2. This three-dimensional complementarity, between the E2 active site and substrate surface, induced by FANCL is central to site-specific monoubiquitination in the FA pathway. Furthermore, the allosteric network of UBE2T can be engineered to enhance FANCL-catalyzed FANCD2-FANCI di-monoubiquitination without compromising site specificity.

Allosteric mechanism for site-specific ubiquitination of FANCD2.,Chaugule VK, Arkinson C, Rennie ML, Kamarainen O, Toth R, Walden H Nat Chem Biol. 2019 Dec 23. pii: 10.1038/s41589-019-0426-z. doi:, 10.1038/s41589-019-0426-z. PMID:31873223^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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:https://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:https://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:https://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:https://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:https://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
↑ Chaugule VK, Arkinson C, Rennie ML, Kamarainen O, Toth R, Walden H. Allosteric mechanism for site-specific ubiquitination of FANCD2. Nat Chem Biol. 2019 Dec 23. pii: 10.1038/s41589-019-0426-z. doi:, 10.1038/s41589-019-0426-z. PMID:31873223 doi:https://dx.doi.org/10.1038/s41589-019-0426-z

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OCA

[1] 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:https://dx.doi.org/10.1016/j.molcel.2006.06.024

[2] 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:https://dx.doi.org/10.1128/MCB.00504-07

[3] 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:https://dx.doi.org/10.1016/j.molcel.2008.12.003

[4] 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:https://dx.doi.org/10.1158/0008-5472.CAN-09-1809

[5] 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:https://dx.doi.org/10.1074/jbc.C109.038075

[6] 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

[7] Chaugule VK, Arkinson C, Rennie ML, Kamarainen O, Toth R, Walden H. Allosteric mechanism for site-specific ubiquitination of FANCD2. Nat Chem Biol. 2019 Dec 23. pii: 10.1038/s41589-019-0426-z. doi:, 10.1038/s41589-019-0426-z. PMID:31873223 doi:https://dx.doi.org/10.1038/s41589-019-0426-z

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@@ Line 3: / Line 3: @@
 <StructureSection load='6r75' size='340' side='right'caption='[[6r75]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6r75]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R75 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6R75 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6r75]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6R75 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6R75 FirstGlance]. <br>
-</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">UBE2T, HSPC150, PIG50 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/E2_ubiquitin-conjugating_enzyme E2 ubiquitin-conjugating enzyme], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.2.23 2.3.2.23] </span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6r75 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r75 OCA], [https://pdbe.org/6r75 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6r75 RCSB], [https://www.ebi.ac.uk/pdbsum/6r75 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6r75 ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6r75 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r75 OCA], [http://pdbe.org/6r75 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6r75 RCSB], [http://www.ebi.ac.uk/pdbsum/6r75 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6r75 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/UBE2T_HUMAN 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.<ref>PMID:16916645</ref> <ref>PMID:17938197</ref> <ref>PMID:19111657</ref> <ref>PMID:19887602</ref> <ref>PMID:19589784</ref> <ref>PMID:20061386</ref>
+[https://www.uniprot.org/uniprot/UBE2T_HUMAN 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.<ref>PMID:16916645</ref> <ref>PMID:17938197</ref> <ref>PMID:19111657</ref> <ref>PMID:19887602</ref> <ref>PMID:19589784</ref> <ref>PMID:20061386</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 19: / Line 18: @@
 </div>
 <div class="pdbe-citations 6r75" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[3D structures of ubiquitin conjugating enzyme|3D structures of ubiquitin conjugating enzyme]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: E2 ubiquitin-conjugating enzyme]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Arkinson, C]]
+[[Category: Arkinson C]]
-[[Category: Chaugule, V K]]
+[[Category: Chaugule VK]]
-[[Category: Kamarainen, O]]
+[[Category: Kamarainen O]]
-[[Category: Rennie, M L]]
+[[Category: Rennie ML]]
-[[Category: Toth, R]]
+[[Category: Toth R]]
-[[Category: Walden, H]]
+[[Category: Walden H]]
-[[Category: Allostery]]
-[[Category: Dna repair]]
-[[Category: E2]]
-[[Category: Ligase]]
-[[Category: Ubiquitination]]

6r75: Difference between revisions

Latest revision as of 12:16, 24 January 2024

Crystal structure of human Ube2T E54R mutant

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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