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| | ==Crystal structure of the UBR-box domain from UBR2 in complex with RLWS N-degron== | | ==Crystal structure of the UBR-box domain from UBR2 in complex with RLWS N-degron== |
| - | <StructureSection load='5tda' size='340' side='right' caption='[[5tda]], [[Resolution|resolution]] 0.79Å' scene=''> | + | <StructureSection load='5tda' size='340' side='right'caption='[[5tda]], [[Resolution|resolution]] 0.79Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5tda]] 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=5TDA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TDA FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5tda]] is a 2 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=5TDA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TDA FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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]] 0.79Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5tdb|5tdb]], [[5tdc|5tdc]], [[5tdd|5tdd]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">UBR2, C6orf133, KIAA0349 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5tda FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tda OCA], [https://pdbe.org/5tda PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tda RCSB], [https://www.ebi.ac.uk/pdbsum/5tda PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tda 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=5tda FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tda OCA], [http://pdbe.org/5tda PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tda RCSB], [http://www.ebi.ac.uk/pdbsum/5tda PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tda ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/UBR2_HUMAN UBR2_HUMAN]] E3 ubiquitin-protein ligase which is a component of the N-end rule pathway. Recognizes and binds to proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their ubiquitination and subsequent degradation. Plays a critical role in chromatin inactivation and chromosome-wide transcriptional silencing during meiosis via ubiquitination of histone H2A. Binds leucine and is a negative regulator of the leucine-mTOR signaling pathway, thereby controlling cell growth.<ref>PMID:15548684</ref> <ref>PMID:20298436</ref> <ref>PMID:20835242</ref> | + | [https://www.uniprot.org/uniprot/UBR2_HUMAN UBR2_HUMAN] E3 ubiquitin-protein ligase which is a component of the N-end rule pathway. Recognizes and binds to proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their ubiquitination and subsequent degradation. Plays a critical role in chromatin inactivation and chromosome-wide transcriptional silencing during meiosis via ubiquitination of histone H2A. Binds leucine and is a negative regulator of the leucine-mTOR signaling pathway, thereby controlling cell growth.<ref>PMID:15548684</ref> <ref>PMID:20298436</ref> <ref>PMID:20835242</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5tda" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5tda" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Gehring, K]] | + | [[Category: Large Structures]] |
| - | [[Category: Kozlov, G]] | + | [[Category: Gehring K]] |
| - | [[Category: Munoz-Escobar, J]] | + | [[Category: Kozlov G]] |
| - | [[Category: Ligase]]
| + | [[Category: Munoz-Escobar J]] |
| - | [[Category: N-degron]]
| + | |
| - | [[Category: N-end rule]]
| + | |
| - | [[Category: Ubr-box]]
| + | |
| - | [[Category: Zn-finger]]
| + | |
| Structural highlights
Function
UBR2_HUMAN E3 ubiquitin-protein ligase which is a component of the N-end rule pathway. Recognizes and binds to proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their ubiquitination and subsequent degradation. Plays a critical role in chromatin inactivation and chromosome-wide transcriptional silencing during meiosis via ubiquitination of histone H2A. Binds leucine and is a negative regulator of the leucine-mTOR signaling pathway, thereby controlling cell growth.[1] [2] [3]
Publication Abstract from PubMed
The N-end rule pathway controls the half-life of proteins based on their N-terminal residue. Positively charged type 1 N-degrons are recognized by a negatively charged pocket on the Zn finger named the UBR box. Here, we show that the UBR box is rigid, but bound water molecules in the pocket provide the structural plasticity required to bind different positively charged amino acids. Ultra-high-resolution crystal structures of arginine, histidine, and methylated arginine reveal that water molecules mediate the binding of N-degron peptides. Using a high-throughput binding assay and isothermal titration calorimetry, we demonstrate that the UBR box is able to bind methylated arginine and lysine peptides with high affinity and measure the preference for hydrophobic residues in the second position in the N-degron peptide. Finally, we show that the V122L mutation present in Johanson-Blizzard syndrome patients changes the specificity for the second position due to occlusion of the secondary pocket.
Bound Waters Mediate Binding of Diverse Substrates to a Ubiquitin Ligase.,Munoz-Escobar J, Matta-Camacho E, Cho C, Kozlov G, Gehring K Structure. 2017 Mar 27. pii: S0969-2126(17)30064-3. doi:, 10.1016/j.str.2017.03.004. PMID:28392261[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kwak KS, Zhou X, Solomon V, Baracos VE, Davis J, Bannon AW, Boyle WJ, Lacey DL, Han HQ. Regulation of protein catabolism by muscle-specific and cytokine-inducible ubiquitin ligase E3alpha-II during cancer cachexia. Cancer Res. 2004 Nov 15;64(22):8193-8. PMID:15548684 doi:http://dx.doi.org/64/22/8193
- ↑ Kume K, Iizumi Y, Shimada M, Ito Y, Kishi T, Yamaguchi Y, Handa H. Role of N-end rule ubiquitin ligases UBR1 and UBR2 in regulating the leucine-mTOR signaling pathway. Genes Cells. 2010 Apr 1;15(4):339-49. doi: 10.1111/j.1365-2443.2010.01385.x. Epub, 2010 Mar 16. PMID:20298436 doi:http://dx.doi.org/10.1111/j.1365-2443.2010.01385.x
- ↑ Matta-Camacho E, Kozlov G, Li FF, Gehring K. Structural basis of substrate recognition and specificity in the N-end rule pathway. Nat Struct Mol Biol. 2010 Oct;17(10):1182-7. Epub 2010 Sep 12. PMID:20835242 doi:10.1038/nsmb.1894
- ↑ Munoz-Escobar J, Matta-Camacho E, Cho C, Kozlov G, Gehring K. Bound Waters Mediate Binding of Diverse Substrates to a Ubiquitin Ligase. Structure. 2017 Mar 27. pii: S0969-2126(17)30064-3. doi:, 10.1016/j.str.2017.03.004. PMID:28392261 doi:http://dx.doi.org/10.1016/j.str.2017.03.004
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