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| | <StructureSection load='6jx5' size='340' side='right'caption='[[6jx5]], [[Resolution|resolution]] 2.40Å' scene=''> | | <StructureSection load='6jx5' size='340' side='right'caption='[[6jx5]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6jx5]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JX5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6JX5 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6jx5]] is a 3 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=6JX5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6JX5 FirstGlance]. <br> |
| - | </td></tr><tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.2.26 2.3.2.26] </span></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]] 2.402Å</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=6jx5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jx5 OCA], [http://pdbe.org/6jx5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jx5 RCSB], [http://www.ebi.ac.uk/pdbsum/6jx5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jx5 ProSAT]</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=6jx5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jx5 OCA], [https://pdbe.org/6jx5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6jx5 RCSB], [https://www.ebi.ac.uk/pdbsum/6jx5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6jx5 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/AREL1_HUMAN AREL1_HUMAN]] E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Inhibits apoptosis by ubiquitinating and targeting for degradation a number of proapoptotic proteins including DIABLO/SMAC, HTRA2 and SEPT4/ARTS which are released from the mitochondrion into the cytosol following apoptotic stimulation.<ref>PMID:23479728</ref> | + | [https://www.uniprot.org/uniprot/AREL1_HUMAN AREL1_HUMAN] E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Inhibits apoptosis by ubiquitinating and targeting for degradation a number of proapoptotic proteins including DIABLO/SMAC, HTRA2 and SEPT4/ARTS which are released from the mitochondrion into the cytosol following apoptotic stimulation.<ref>PMID:23479728</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Transferase]]
| + | [[Category: Nayak D]] |
| - | [[Category: Nayak, D]] | + | [[Category: Ng J]] |
| - | [[Category: Ng, J]] | + | [[Category: Singh S]] |
| - | [[Category: Singh, S]] | + | [[Category: Sivaraman J]] |
| - | [[Category: Sivaraman, J]] | + | |
| - | [[Category: Apoptosis]]
| + | |
| - | [[Category: Hect domain]]
| + | |
| Structural highlights
Function
AREL1_HUMAN E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Inhibits apoptosis by ubiquitinating and targeting for degradation a number of proapoptotic proteins including DIABLO/SMAC, HTRA2 and SEPT4/ARTS which are released from the mitochondrion into the cytosol following apoptotic stimulation.[1]
Publication Abstract from PubMed
The HECT E3 ligase family comprises three subfamilies: NEDD4 E3 ubiquitin protein ligase (NEDD4), HECT and RLD domain-containing E3 ubiquitin protein ligase (HERC), and "other." Most previous studies have focused on the NEDD4 subfamily. Apoptosis-resistant E3 ligase 1 (AREL1) belongs to "other" subfamily HECT that inhibits apoptosis by ubiquitinating and degrading proapoptotic proteins. Here, we report the crystal structure of the extended HECT domain of AREL1 (436-823 aa) at 2.4 A resolution and its ubiquitination of the proapoptotic protein second mitochondria-derived activator of caspase (SMAC). We found that the extended HECT domain adopts an inverted, T-shaped, bilobed conformation and harbors an additional loop (567-573 aa) absent in all other HECT members. We also show that the N-terminal extended region (436-482 aa) preceding the HECT domain is indispensable for its stability and activity and that without this region, the HECT domain becomes inactive. AREL1 ubiquitinated SMAC, primarily on Lys-62 and Lys-191. We solved the crystal structure of tetrameric form of SMAC to 2.8 A resolution, revealing the Lys-62 and Lys-191 locations. The AREL1 HECT domain assembled Lys-33-, Lys-48- and Lys-63-linked polyubiquitin chains. Moreover, E701A substitution in the AREL1 HECT domain substantially increased its autopolyubiquitination and SMAC ubiquitination activity, whereas deletion of the last three amino acids at the C terminus completely abrogated AREL1 autoubiquitination and reduced SMAC ubiquitination. Finally, an AREL1-specific ubiquitin variant inhibited SMAC ubiquitination in vitro. Our findings may assist in the development of AREL1 inhibitors that block its anti-apoptotic activity in cancer.
Structural insights into a HECT-type E3 ligase AREL1 and its ubiquitination activities in vitro.,Singh S, Ng J, Nayak D, Sivaraman J J Biol Chem. 2019 Nov 15. pii: RA119.010327. doi: 10.1074/jbc.RA119.010327. PMID:31732561[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kim JB, Kim SY, Kim BM, Lee H, Kim I, Yun J, Jo Y, Oh T, Jo Y, Chae HD, Shin DY. Identification of a novel anti-apoptotic E3 ubiquitin ligase that ubiquitinates antagonists of inhibitor of apoptosis proteins SMAC, HtrA2, and ARTS. J Biol Chem. 2013 Apr 26;288(17):12014-21. doi: 10.1074/jbc.M112.436113. Epub, 2013 Mar 11. PMID:23479728 doi:http://dx.doi.org/10.1074/jbc.M112.436113
- ↑ Singh S, Ng J, Nayak D, Sivaraman J. Structural insights into a HECT-type E3 ligase AREL1 and its ubiquitination activities in vitro. J Biol Chem. 2019 Nov 15. pii: RA119.010327. doi: 10.1074/jbc.RA119.010327. PMID:31732561 doi:http://dx.doi.org/10.1074/jbc.RA119.010327
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