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| - | ==THE IDOL-UBE2D COMPLEX MEDIATES STEROL-DEPENDENT DEGRADATION OF THE LDL RECEPTOR== | + | |
| - | <StructureSection load='2yho' size='340' side='right' caption='[[2yho]], [[Resolution|resolution]] 2.10Å' scene=''> | + | ==The IDOL-UBE2D complex mediates sterol-dependent degradation of the LDL receptor== |
| | + | <StructureSection load='2yho' size='340' side='right'caption='[[2yho]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2yho]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YHO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2YHO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2yho]] is a 8 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=2YHO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2YHO FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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]] 2.1Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2yhn|2yhn]], [[2c4p|2c4p]]</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=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Ubiquitin--protein_ligase Ubiquitin--protein ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.2.19 6.3.2.19] </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=2yho FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yho OCA], [https://pdbe.org/2yho PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2yho RCSB], [https://www.ebi.ac.uk/pdbsum/2yho PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2yho 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=2yho FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yho OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2yho RCSB], [http://www.ebi.ac.uk/pdbsum/2yho PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MYLIP_HUMAN MYLIP_HUMAN]] E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of myosin regulatory light chain (MRLC), LDLR, VLDLR and LRP8. Activity depends on E2 enzymes of the UBE2D family. Proteasomal degradation of MRLC leads to inhibit neurite outgrowth in presence of NGF by counteracting the stabilization of MRLC by saposin-like protein (CNPY2/MSAP) and reducing CNPY2-stimulated neurite outgrowth. Acts as a sterol-dependent inhibitor of cellular cholesterol uptake by mediating ubiquitination and subsequent degradation of LDLR.<ref>PMID:10593918</ref> <ref>PMID:14550572</ref> <ref>PMID:12826659</ref> <ref>PMID:19520913</ref> <ref>PMID:20427281</ref> <ref>PMID:22109552</ref> [[http://www.uniprot.org/uniprot/UB2D1_HUMAN UB2D1_HUMAN]] Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-48'-linked polyubiquitination. Mediates the selective degradation of short-lived and abnormal proteins. Functions in the E6/E6-AP-induced ubiquitination of p53/TP53. Mediates ubiquitination of PEX5 and auto-ubiquitination of STUB1, TRAF6 and TRIM63/MURF1. Ubiquitinates STUB1-associated HSP90AB1 in vitro. Lacks inherent specificity for any particular lysine residue of ubiquitin. Essential for viral activation of IRF3. Mediates polyubiquitination of CYP3A4.<ref>PMID:18042044</ref> <ref>PMID:18359941</ref> <ref>PMID:19103148</ref> <ref>PMID:19854139</ref> <ref>PMID:20061386</ref> | + | [https://www.uniprot.org/uniprot/MYLIP_HUMAN MYLIP_HUMAN] E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of myosin regulatory light chain (MRLC), LDLR, VLDLR and LRP8. Activity depends on E2 enzymes of the UBE2D family. Proteasomal degradation of MRLC leads to inhibit neurite outgrowth in presence of NGF by counteracting the stabilization of MRLC by saposin-like protein (CNPY2/MSAP) and reducing CNPY2-stimulated neurite outgrowth. Acts as a sterol-dependent inhibitor of cellular cholesterol uptake by mediating ubiquitination and subsequent degradation of LDLR.<ref>PMID:10593918</ref> <ref>PMID:14550572</ref> <ref>PMID:12826659</ref> <ref>PMID:19520913</ref> <ref>PMID:20427281</ref> <ref>PMID:22109552</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 2yho" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Ubiquitin conjugating enzyme|Ubiquitin conjugating enzyme]] | + | *[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]] |
| - | *[[Ubiquitin protein ligase|Ubiquitin protein ligase]] | + | *[[3D structures of ubiquitin conjugating enzyme|3D structures of ubiquitin conjugating enzyme]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Ubiquitin--protein ligase]] | + | [[Category: Large Structures]] |
| - | [[Category: Fairall, L]] | + | [[Category: Fairall L]] |
| - | [[Category: Goult, B T]] | + | [[Category: Goult BT]] |
| - | [[Category: Millard, C J]] | + | [[Category: Millard CJ]] |
| - | [[Category: Schwabe, J W.R]] | + | [[Category: Schwabe JWR]] |
| - | [[Category: Tontonoz, P]] | + | [[Category: Tontonoz P]] |
| - | [[Category: E2 ligase-e3 ligase complex]]
| + | |
| - | [[Category: Ligase]]
| + | |
| - | [[Category: Ring zinc-finger]]
| + | |
| - | [[Category: Ubl conjugation pathway]]
| + | |
| Structural highlights
Function
MYLIP_HUMAN E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of myosin regulatory light chain (MRLC), LDLR, VLDLR and LRP8. Activity depends on E2 enzymes of the UBE2D family. Proteasomal degradation of MRLC leads to inhibit neurite outgrowth in presence of NGF by counteracting the stabilization of MRLC by saposin-like protein (CNPY2/MSAP) and reducing CNPY2-stimulated neurite outgrowth. Acts as a sterol-dependent inhibitor of cellular cholesterol uptake by mediating ubiquitination and subsequent degradation of LDLR.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
We previously identified the E3 ubiquitin ligase IDOL as a sterol-dependent regulator of the LDL receptor (LDLR). The molecular pathway underlying IDOL action, however, remains to be determined. Here we report the identification and biochemical and structural characterization of an E2-E3 ubiquitin ligase complex for LDLR degradation. We identified the UBE2D family (UBE2D1-4) as E2 partners for IDOL that support both autoubiquitination and IDOL-dependent ubiquitination of the LDLR in a cell-free system. NMR chemical shift mapping and a 2.1 A crystal structure of the IDOL RING domain-UBE2D1 complex revealed key interactions between the dimeric IDOL protein and the E2 enzyme. Analysis of the IDOL-UBE2D1 interface also defined the stereochemical basis for the selectivity of IDOL for UBE2Ds over other E2 ligases. Structure-based mutations that inhibit IDOL dimerization or IDOL-UBE2D interaction block IDOL-dependent LDLR ubiquitination and degradation. Furthermore, expression of a dominant-negative UBE2D enzyme inhibits the ability of IDOL to degrade the LDLR in cells. These results identify the IDOL-UBE2D complex as an important determinant of LDLR activity, and provide insight into molecular mechanisms underlying the regulation of cholesterol uptake.
The IDOL-UBE2D complex mediates sterol-dependent degradation of the LDL receptor.,Zhang L, Fairall L, Goult BT, Calkin AC, Hong C, Millard CJ, Tontonoz P, Schwabe JW Genes Dev. 2011 Jun 15;25(12):1262-74. PMID:21685362[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Olsson PA, Korhonen L, Mercer EA, Lindholm D. MIR is a novel ERM-like protein that interacts with myosin regulatory light chain and inhibits neurite outgrowth. J Biol Chem. 1999 Dec 17;274(51):36288-92. PMID:10593918
- ↑ Bornhauser BC, Johansson C, Lindholm D. Functional activities and cellular localization of the ezrin, radixin, moesin (ERM) and RING zinc finger domains in MIR. FEBS Lett. 2003 Oct 9;553(1-2):195-9. PMID:14550572
- ↑ Bornhauser BC, Olsson PA, Lindholm D. MSAP is a novel MIR-interacting protein that enhances neurite outgrowth and increases myosin regulatory light chain. J Biol Chem. 2003 Sep 12;278(37):35412-20. Epub 2003 Jun 24. PMID:12826659 doi:10.1074/jbc.M306271200
- ↑ Zelcer N, Hong C, Boyadjian R, Tontonoz P. LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science. 2009 Jul 3;325(5936):100-4. doi: 10.1126/science.1168974. Epub 2009 Jun , 11. PMID:19520913 doi:10.1126/science.1168974
- ↑ Hong C, Duit S, Jalonen P, Out R, Scheer L, Sorrentino V, Boyadjian R, Rodenburg KW, Foley E, Korhonen L, Lindholm D, Nimpf J, van Berkel TJ, Tontonoz P, Zelcer N. The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2. J Biol Chem. 2010 Jun 25;285(26):19720-6. doi: 10.1074/jbc.M110.123729. Epub 2010, Apr 28. PMID:20427281 doi:10.1074/jbc.M110.123729
- ↑ Calkin AC, Goult BT, Zhang L, Fairall L, Hong C, Schwabe JW, Tontonoz P. FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors. Proc Natl Acad Sci U S A. 2011 Dec 13;108(50):20107-12. doi:, 10.1073/pnas.1111589108. Epub 2011 Nov 22. PMID:22109552 doi:10.1073/pnas.1111589108
- ↑ Zhang L, Fairall L, Goult BT, Calkin AC, Hong C, Millard CJ, Tontonoz P, Schwabe JW. The IDOL-UBE2D complex mediates sterol-dependent degradation of the LDL receptor. Genes Dev. 2011 Jun 15;25(12):1262-74. PMID:21685362 doi:10.1101/gad.2056211
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