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| | ==Solution structure of RNF126 N-terminal zinc finger domain in complex with BAG6 Ubiquitin-like domain== | | ==Solution structure of RNF126 N-terminal zinc finger domain in complex with BAG6 Ubiquitin-like domain== |
| - | <StructureSection load='2n9p' size='340' side='right'caption='[[2n9p]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | + | <StructureSection load='2n9p' size='340' side='right'caption='[[2n9p]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2n9p]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N9P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2N9P FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2n9p]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2N9P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2N9P FirstGlance]. <br> |
| | </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> | | </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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2n9o|2n9o]]</div></td></tr> | |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RNF126 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), BAG6, BAT3, G3 ([https://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=2n9p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n9p OCA], [https://pdbe.org/2n9p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2n9p RCSB], [https://www.ebi.ac.uk/pdbsum/2n9p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2n9p 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=2n9p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2n9p OCA], [https://pdbe.org/2n9p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2n9p RCSB], [https://www.ebi.ac.uk/pdbsum/2n9p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2n9p ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/RN126_HUMAN RN126_HUMAN]] E3 ubiquitin-protein ligase that regulates several biological processes through ubiquitination of various target proteins. Depending on the associated E2 ligase, mediates 'Lys-48'- and 'Lys-63'-linked polyubiquitination of substrates. Through their polyubiquitination, may play a role in the endosomal sorting and degradation of several membrane receptors including EGFR, FLT3, MET and CXCR4. May also be part of a BAG6-dependent quality control process ensuring that proteins of the secretory pathway that are mislocalized to the cytosol are degraded by the proteasome. May provide the ubiquitin ligase activity associated with the BAG6 complex and be responsible for ubiquitination of the mislocalized proteins and their targeting to the proteasome (PubMed:24981174). May also play a role in the endosomal recycling of IGF2R, the cation-independent mannose-6-phosphate receptor (PubMed:24275455). By ubiquitinating CDKN1A/p21 and targeting it for degradation, may also promote cell proliferation (PubMed:23026136). May monoubiquitinate AICDA (PubMed:23277564).[UniProtKB:Q91YL2]<ref>PMID:23277564</ref> <ref>PMID:24275455</ref> <ref>PMID:24981174</ref> <ref>PMID:23026136</ref> [[https://www.uniprot.org/uniprot/BAG6_HUMAN BAG6_HUMAN]] Chaperone that plays a key role in various processes such as apoptosis, insertion of tail-anchored (TA) membrane proteins to the endoplasmic reticulum membrane and regulation of chromatin. Acts in part by regulating stability of proteins and their degradation by the proteasome. Participates in endoplasmic reticulum stress-induced apoptosis via its interaction with AIFM1/AIF by regulating AIFM1/AIF stability and preventing its degradation. Also required during spermatogenesis for synaptonemal complex assembly via its interaction with HSPA2, by inhibiting polyubiquitination and subsequent proteasomal degradation of HSPA2. Required for selective ubiquitin-mediated degradation of defective nascent chain polypeptides by the proteasome. In this context, may play a role in immuno-proteasomes to generate antigenic peptides via targeted degradation, thereby playing a role in antigen presentation in immune response. Key component of the BAG6/BAT3 complex, a cytosolic multiprotein complex involved in the post-translational delivery of tail-anchored (TA) membrane proteins to the endoplasmic reticulum membrane. TA membrane proteins, also named type II transmembrane proteins, contain a single C-terminal transmembrane region. BAG6/BAT3 acts by facilitating TA membrane proteins capture by ASNA1/TRC40: it is recruited to ribosomes synthesizing membrane proteins, interacts with the transmembrane region of newly released TA proteins and transfers them to ASNA1/TRC40 for targeting to the endoplasmic reticulum membrane.<ref>PMID:14960581</ref> <ref>PMID:17403783</ref> <ref>PMID:18055229</ref> <ref>PMID:18765639</ref> <ref>PMID:18852879</ref> <ref>PMID:20516149</ref> <ref>PMID:20676083</ref> Involved in DNA damage-induced apoptosis: following DNA damage, accumulates in the nucleus and forms a complex with p300/EP300, enhancing p300/EP300-mediated p53/TP53 acetylation leading to increase p53/TP53 transcriptional activity. When nuclear, may also act as a component of some chromatin regulator complex that regulates histone 3 'Lys-4' dimethylation (H3K4me2).<ref>PMID:14960581</ref> <ref>PMID:17403783</ref> <ref>PMID:18055229</ref> <ref>PMID:18765639</ref> <ref>PMID:18852879</ref> <ref>PMID:20516149</ref> <ref>PMID:20676083</ref> Can be released from tumor and dendritic cells in membrane vesicles or exosomes, and engage NCR3 thereby promoting natural killer cell (NK) activation and cytotoxicity.<ref>PMID:14960581</ref> <ref>PMID:17403783</ref> <ref>PMID:18055229</ref> <ref>PMID:18765639</ref> <ref>PMID:18852879</ref> <ref>PMID:20516149</ref> <ref>PMID:20676083</ref>
| + | [https://www.uniprot.org/uniprot/RN126_HUMAN RN126_HUMAN] E3 ubiquitin-protein ligase that regulates several biological processes through ubiquitination of various target proteins. Depending on the associated E2 ligase, mediates 'Lys-48'- and 'Lys-63'-linked polyubiquitination of substrates. Through their polyubiquitination, may play a role in the endosomal sorting and degradation of several membrane receptors including EGFR, FLT3, MET and CXCR4. May also be part of a BAG6-dependent quality control process ensuring that proteins of the secretory pathway that are mislocalized to the cytosol are degraded by the proteasome. May provide the ubiquitin ligase activity associated with the BAG6 complex and be responsible for ubiquitination of the mislocalized proteins and their targeting to the proteasome (PubMed:24981174). May also play a role in the endosomal recycling of IGF2R, the cation-independent mannose-6-phosphate receptor (PubMed:24275455). By ubiquitinating CDKN1A/p21 and targeting it for degradation, may also promote cell proliferation (PubMed:23026136). May monoubiquitinate AICDA (PubMed:23277564).[UniProtKB:Q91YL2]<ref>PMID:23277564</ref> <ref>PMID:24275455</ref> <ref>PMID:24981174</ref> <ref>PMID:23026136</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: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Isaacson, R L]] | + | [[Category: Isaacson RL]] |
| - | [[Category: Krysztofinska, E M]] | + | [[Category: Krysztofinska EM]] |
| - | [[Category: Martinez-Lumbreras, S]] | + | [[Category: Martinez-Lumbreras S]] |
| - | [[Category: Thapaliya, A]] | + | [[Category: Thapaliya A]] |
| - | [[Category: E3 ligase]]
| + | |
| - | [[Category: Ligase]]
| + | |
| - | [[Category: Zinc finger]]
| + | |
| Structural highlights
Function
RN126_HUMAN E3 ubiquitin-protein ligase that regulates several biological processes through ubiquitination of various target proteins. Depending on the associated E2 ligase, mediates 'Lys-48'- and 'Lys-63'-linked polyubiquitination of substrates. Through their polyubiquitination, may play a role in the endosomal sorting and degradation of several membrane receptors including EGFR, FLT3, MET and CXCR4. May also be part of a BAG6-dependent quality control process ensuring that proteins of the secretory pathway that are mislocalized to the cytosol are degraded by the proteasome. May provide the ubiquitin ligase activity associated with the BAG6 complex and be responsible for ubiquitination of the mislocalized proteins and their targeting to the proteasome (PubMed:24981174). May also play a role in the endosomal recycling of IGF2R, the cation-independent mannose-6-phosphate receptor (PubMed:24275455). By ubiquitinating CDKN1A/p21 and targeting it for degradation, may also promote cell proliferation (PubMed:23026136). May monoubiquitinate AICDA (PubMed:23277564).[UniProtKB:Q91YL2][1] [2] [3] [4]
Publication Abstract from PubMed
RNF126 is an E3 ubiquitin ligase that collaborates with the BAG6 sortase complex to ubiquitinate hydrophobic substrates in the cytoplasm that are destined for proteasomal recycling. Composed of a trimeric complex of BAG6, TRC35 and UBL4A the BAG6 sortase is also associated with SGTA, a co-chaperone from which it can obtain hydrophobic substrates. Here we solve the solution structure of the RNF126 zinc finger domain in complex with the BAG6 UBL domain. We also characterise an interaction between RNF126 and UBL4A and analyse the competition between SGTA and RNF126 for the N-terminal BAG6 binding site. This work sheds light on the sorting mechanism of the BAG6 complex and its accessory proteins which, together, decide the fate of stray hydrophobic proteins in the aqueous cytoplasm.
Structural and functional insights into the E3 ligase, RNF126.,Krysztofinska EM, Martinez-Lumbreras S, Thapaliya A, Evans NJ, High S, Isaacson RL Sci Rep. 2016 May 19;6:26433. doi: 10.1038/srep26433. PMID:27193484[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Delker RK, Zhou Y, Strikoudis A, Stebbins CE, Papavasiliou FN. Solubility-based genetic screen identifies RING finger protein 126 as an E3 ligase for activation-induced cytidine deaminase. Proc Natl Acad Sci U S A. 2013 Jan 15;110(3):1029-34. doi:, 10.1073/pnas.1214538110. Epub 2012 Dec 31. PMID:23277564 doi:http://dx.doi.org/10.1073/pnas.1214538110
- ↑ Smith CJ, McGlade CJ. The ubiquitin ligase RNF126 regulates the retrograde sorting of the cation-independent mannose 6-phosphate receptor. Exp Cell Res. 2014 Jan 15;320(2):219-32. doi: 10.1016/j.yexcr.2013.11.013. Epub, 2013 Nov 23. PMID:24275455 doi:http://dx.doi.org/10.1016/j.yexcr.2013.11.013
- ↑ Rodrigo-Brenni MC, Gutierrez E, Hegde RS. Cytosolic quality control of mislocalized proteins requires RNF126 recruitment to Bag6. Mol Cell. 2014 Jul 17;55(2):227-37. doi: 10.1016/j.molcel.2014.05.025. Epub 2014 , Jun 26. PMID:24981174 doi:http://dx.doi.org/10.1016/j.molcel.2014.05.025
- ↑ Zhi X, Zhao D, Wang Z, Zhou Z, Wang C, Chen W, Liu R, Chen C. E3 ubiquitin ligase RNF126 promotes cancer cell proliferation by targeting the tumor suppressor p21 for ubiquitin-mediated degradation. Cancer Res. 2013 Jan 1;73(1):385-94. doi: 10.1158/0008-5472.CAN-12-0562. Epub, 2012 Oct 1. PMID:23026136 doi:http://dx.doi.org/10.1158/0008-5472.CAN-12-0562
- ↑ Krysztofinska EM, Martinez-Lumbreras S, Thapaliya A, Evans NJ, High S, Isaacson RL. Structural and functional insights into the E3 ligase, RNF126. Sci Rep. 2016 May 19;6:26433. doi: 10.1038/srep26433. PMID:27193484 doi:http://dx.doi.org/10.1038/srep26433
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