6s98

From Proteopedia

(Difference between revisions)

Revision as of 07:33, 4 November 2020

Crystal structure of the catalytic domain of UBE2S WT.

Structural highlights

6s98 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
NonStd Res:
Related:	1zdn, 6qhk, 6qh3, 6s96
Gene:	UBE2S, E2EPF, OK/SW-cl.73 (HUMAN)
Activity:	E2 ubiquitin-conjugating enzyme, with EC number 2.3.2.23
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[UBE2S_HUMAN] Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. Catalyzes 'Lys-11'-linked polyubiquitination. Acts as an essential factor of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated ubiquitin ligase that controls progression through mitosis. Acts by specifically elongating 'Lys-11'-linked polyubiquitin chains initiated by the E2 enzyme UBE2C/UBCH10 on APC/C substrates, enhancing the degradation of APC/C substrates by the proteasome and promoting mitotic exit. Also acts by elongating ubiquitin chains initiated by the E2 enzyme UBE2D1/UBCH5 in vitro; it is however unclear whether UBE2D1/UBCH5 acts as a E2 enzyme for the APC/C in vivo. Also involved in ubiquitination and subsequent degradation of VHL, resulting in an accumulation of HIF1A. In vitro able to promote polyubiquitination using all 7 ubiquitin Lys residues, except 'Lys-48'-linked polyubiquitination.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

At the heart of protein ubiquitination cascades, ubiquitin-conjugating enzymes (E2s) form reactive ubiquitin-thioester intermediates to enable efficient transfer of ubiquitin to cellular substrates. The precise regulation of E2s is thus crucial for cellular homeostasis, and their deregulation is frequently associated with tumorigenesis. In addition to driving substrate ubiquitination together with ubiquitin ligases (E3s), many E2s can also autoubiquitinate, thereby promoting their own proteasomal turnover. To investigate the mechanisms that balance these disparate activities, we dissected the regulatory dynamics of UBE2S, a human APC/C-associated E2 that ensures the faithful ubiquitination of cell cycle regulators during mitosis. We uncovered a dimeric state of UBE2S that confers autoinhibition by blocking a catalytically critical ubiquitin binding site. Dimerization is stimulated by the lysine-rich carboxyl-terminal extension of UBE2S that is also required for the recruitment of this E2 to the APC/C and is autoubiquitinated as substrate abundance becomes limiting. Consistent with this mechanism, we found that dimerization-deficient UBE2S turned over more rapidly in cells and did not promote mitotic slippage during prolonged drug-induced mitotic arrest. We propose that dimerization attenuates the autoubiquitination-induced turnover of UBE2S when the APC/C is not fully active. More broadly, our data illustrate how the use of mutually exclusive macromolecular interfaces enables modulation of both the activities and the abundance of E2s in cells to facilitate precise ubiquitin signaling.

Dimerization regulates the human APC/C-associated ubiquitin-conjugating enzyme UBE2S.,Liess AKL, Kucerova A, Schweimer K, Schlesinger D, Dybkov O, Urlaub H, Mansfeld J, Lorenz S Sci Signal. 2020 Oct 20;13(654). pii: 13/654/eaba8208. doi:, 10.1126/scisignal.aba8208. PMID:33082289^[6]

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

References

↑ Jung CR, Hwang KS, Yoo J, Cho WK, Kim JM, Kim WH, Im DS. E2-EPF UCP targets pVHL for degradation and associates with tumor growth and metastasis. Nat Med. 2006 Jul;12(7):809-16. Epub 2006 Jul 2. PMID:16819549 doi:http://dx.doi.org/10.1038/nm1440
↑ Garnett MJ, Mansfeld J, Godwin C, Matsusaka T, Wu J, Russell P, Pines J, Venkitaraman AR. UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit. Nat Cell Biol. 2009 Nov;11(11):1363-9. doi: 10.1038/ncb1983. Epub 2009 Oct 11. PMID:19820702 doi:http://dx.doi.org/10.1038/ncb1983
↑ Williamson A, Wickliffe KE, Mellone BG, Song L, Karpen GH, Rape M. Identification of a physiological E2 module for the human anaphase-promoting complex. Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18213-8. doi:, 10.1073/pnas.0907887106. Epub 2009 Oct 12. PMID:19822757 doi:http://dx.doi.org/10.1073/pnas.0907887106
↑ 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
↑ Bremm A, Freund SM, Komander D. Lys11-linked ubiquitin chains adopt compact conformations and are preferentially hydrolyzed by the deubiquitinase Cezanne. Nat Struct Mol Biol. 2010 Aug;17(8):939-47. Epub 2010 Jul 11. PMID:20622874 doi:10.1038/nsmb.1873
↑ Liess AKL, Kucerova A, Schweimer K, Schlesinger D, Dybkov O, Urlaub H, Mansfeld J, Lorenz S. Dimerization regulates the human APC/C-associated ubiquitin-conjugating enzyme UBE2S. Sci Signal. 2020 Oct 20;13(654). pii: 13/654/eaba8208. doi:, 10.1126/scisignal.aba8208. PMID:33082289 doi:http://dx.doi.org/10.1126/scisignal.aba8208

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6s98"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the catalytic domain of UBE2S WT.==
-<StructureSection load='6s98' size='340' side='right'caption='[[6s98]]' scene=''>
+<StructureSection load='6s98' size='340' side='right'caption='[[6s98]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6S98 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6S98 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6s98]] is a 2 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=6S98 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6S98 FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6s98 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6s98 OCA], [http://pdbe.org/6s98 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6s98 RCSB], [http://www.ebi.ac.uk/pdbsum/6s98 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6s98 ProSAT]</span></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
+<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=OCS:CYSTEINESULFONIC+ACID'>OCS</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1zdn|1zdn]], [[6qhk|6qhk]], [[6qh3|6qh3]], [[6s96|6s96]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">UBE2S, E2EPF, OK/SW-cl.73 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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'>[http://proteopedia.org/fgij/fg.htm?mol=6s98 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6s98 OCA], [http://pdbe.org/6s98 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6s98 RCSB], [http://www.ebi.ac.uk/pdbsum/6s98 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6s98 ProSAT]</span></td></tr>
 </table>
+== Function ==
+[[http://www.uniprot.org/uniprot/UBE2S_HUMAN UBE2S_HUMAN]] Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. Catalyzes 'Lys-11'-linked polyubiquitination. Acts as an essential factor of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated ubiquitin ligase that controls progression through mitosis. Acts by specifically elongating 'Lys-11'-linked polyubiquitin chains initiated by the E2 enzyme UBE2C/UBCH10 on APC/C substrates, enhancing the degradation of APC/C substrates by the proteasome and promoting mitotic exit. Also acts by elongating ubiquitin chains initiated by the E2 enzyme UBE2D1/UBCH5 in vitro; it is however unclear whether UBE2D1/UBCH5 acts as a E2 enzyme for the APC/C in vivo. Also involved in ubiquitination and subsequent degradation of VHL, resulting in an accumulation of HIF1A. In vitro able to promote polyubiquitination using all 7 ubiquitin Lys residues, except 'Lys-48'-linked polyubiquitination.<ref>PMID:16819549</ref> <ref>PMID:19820702</ref> <ref>PMID:19822757</ref> <ref>PMID:20061386</ref> <ref>PMID:20622874</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+At the heart of protein ubiquitination cascades, ubiquitin-conjugating enzymes (E2s) form reactive ubiquitin-thioester intermediates to enable efficient transfer of ubiquitin to cellular substrates. The precise regulation of E2s is thus crucial for cellular homeostasis, and their deregulation is frequently associated with tumorigenesis. In addition to driving substrate ubiquitination together with ubiquitin ligases (E3s), many E2s can also autoubiquitinate, thereby promoting their own proteasomal turnover. To investigate the mechanisms that balance these disparate activities, we dissected the regulatory dynamics of UBE2S, a human APC/C-associated E2 that ensures the faithful ubiquitination of cell cycle regulators during mitosis. We uncovered a dimeric state of UBE2S that confers autoinhibition by blocking a catalytically critical ubiquitin binding site. Dimerization is stimulated by the lysine-rich carboxyl-terminal extension of UBE2S that is also required for the recruitment of this E2 to the APC/C and is autoubiquitinated as substrate abundance becomes limiting. Consistent with this mechanism, we found that dimerization-deficient UBE2S turned over more rapidly in cells and did not promote mitotic slippage during prolonged drug-induced mitotic arrest. We propose that dimerization attenuates the autoubiquitination-induced turnover of UBE2S when the APC/C is not fully active. More broadly, our data illustrate how the use of mutually exclusive macromolecular interfaces enables modulation of both the activities and the abundance of E2s in cells to facilitate precise ubiquitin signaling.
+Dimerization regulates the human APC/C-associated ubiquitin-conjugating enzyme UBE2S.,Liess AKL, Kucerova A, Schweimer K, Schlesinger D, Dybkov O, Urlaub H, Mansfeld J, Lorenz S Sci Signal. 2020 Oct 20;13(654). pii: 13/654/eaba8208. doi:, 10.1126/scisignal.aba8208. PMID:33082289<ref>PMID:33082289</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6s98" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: E2 ubiquitin-conjugating enzyme]]
+[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Liess AKL]]
+[[Category: Liess, A K.L]]
-[[Category: Lorenz S]]
+[[Category: Lorenz, S]]
+[[Category: Catalytic domain]]
+[[Category: Human e2]]
+[[Category: Transferase]]

6s98

From Proteopedia

Revision as of 07:33, 4 November 2020

Crystal structure of the catalytic domain of UBE2S WT.

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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