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| | <StructureSection load='5ep6' size='340' side='right'caption='[[5ep6]], [[Resolution|resolution]] 1.45Å' scene=''> | | <StructureSection load='5ep6' size='340' side='right'caption='[[5ep6]], [[Resolution|resolution]] 1.45Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ep6]] is a 4 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=5EP6 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5EP6 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ep6]] is a 4 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=5EP6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EP6 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 1.451Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AZI2, NAP1, TBKBP2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), TBK1, NAK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=5ep6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ep6 OCA], [https://pdbe.org/5ep6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ep6 RCSB], [https://www.ebi.ac.uk/pdbsum/5ep6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ep6 ProSAT]</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=5ep6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ep6 OCA], [http://pdbe.org/5ep6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ep6 RCSB], [http://www.ebi.ac.uk/pdbsum/5ep6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ep6 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/AZI2_HUMAN AZI2_HUMAN]] Adapter protein which binds TBK1 and IKBKE playing a role in antiviral innate immunity. Activates serine/threonine-protein kinase TBK1 and facilitates its oligomerization. Enhances the phosphorylation of NF-kappa-B p65 subunit RELA by TBK1. Promotes TBK1-induced as well as TNF-alpha or PMA-induced activation of NF-kappa-B. Participates in IFNB promoter activation via TICAM1.<ref>PMID:14560022</ref> <ref>PMID:15611223</ref> <ref>PMID:21931631</ref> [[http://www.uniprot.org/uniprot/TBK1_HUMAN TBK1_HUMAN]] Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents. Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro-inflammatory and antiviral genes including IFN-alpha and IFN-beta. In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including FADD, TRADD, MAVS or SINTBAD can be recruited to the TBK1-containing-complexes. Under particular conditions, functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus. Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy. Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C. Phosphorylates and activates AKT1. Phosphorylates Borna disease virus (BDV) P protein.<ref>PMID:10581243</ref> <ref>PMID:10783893</ref> <ref>PMID:11839743</ref> <ref>PMID:12692549</ref> <ref>PMID:12702806</ref> <ref>PMID:14703513</ref> <ref>PMID:15485837</ref> <ref>PMID:15489227</ref> <ref>PMID:15367631</ref> <ref>PMID:18583960</ref> <ref>PMID:21270402</ref> <ref>PMID:21464307</ref> <ref>PMID:21617041</ref> <ref>PMID:21138416</ref> | + | [https://www.uniprot.org/uniprot/AZI2_HUMAN AZI2_HUMAN] Adapter protein which binds TBK1 and IKBKE playing a role in antiviral innate immunity. Activates serine/threonine-protein kinase TBK1 and facilitates its oligomerization. Enhances the phosphorylation of NF-kappa-B p65 subunit RELA by TBK1. Promotes TBK1-induced as well as TNF-alpha or PMA-induced activation of NF-kappa-B. Participates in IFNB promoter activation via TICAM1.<ref>PMID:14560022</ref> <ref>PMID:15611223</ref> <ref>PMID:21931631</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | Optineurin is an important autophagy receptor involved in several selective autophagy processes, during which its function is regulated by TBK1. Mutations of optineurin and TBK1 are both associated with neurodegenerative diseases. However, the mechanistic basis underlying the specific interaction between optineurin and TBK1 is still elusive. Here we determine the crystal structures of optineurin/TBK1 complex and the related NAP1/TBK1 complex, uncovering the detailed molecular mechanism governing the optineurin and TBK1 interaction, and revealing a general binding mode between TBK1 and its associated adaptor proteins. In addition, we demonstrate that the glaucoma-associated optineurin E50K mutation not only enhances the interaction between optineurin and TBK1 but also alters the oligomeric state of optineurin, and the ALS-related TBK1 E696K mutation specifically disrupts the optineurin/TBK1 complex formation but has little effect on the NAP1/TBK1 complex. Thus, our study provides mechanistic insights into those currently known disease-causing optineurin and TBK1 mutations found in patients.
| + | |
| - | | + | |
| - | Structural insights into the interaction and disease mechanism of neurodegenerative disease-associated optineurin and TBK1 proteins.,Li F, Xie X, Wang Y, Liu J, Cheng X, Guo Y, Gong Y, Hu S, Pan L Nat Commun. 2016 Sep 13;7:12708. doi: 10.1038/ncomms12708. PMID:27620379<ref>PMID:27620379</ref>
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| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 5ep6" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Non-specific serine/threonine protein kinase]]
| + | [[Category: Li F]] |
| - | [[Category: Li, F]] | + | [[Category: Liu J]] |
| - | [[Category: Liu, J]] | + | [[Category: Pan L]] |
| - | [[Category: Pan, L]] | + | [[Category: Xie X]] |
| - | [[Category: Xie, X]] | + | |
| - | [[Category: Calcoco2]]
| + | |
| - | [[Category: Nap1]]
| + | |
| - | [[Category: Protein binding-transferase complex]]
| + | |
| - | [[Category: Tbk1]]
| + | |
| Structural highlights
Function
AZI2_HUMAN Adapter protein which binds TBK1 and IKBKE playing a role in antiviral innate immunity. Activates serine/threonine-protein kinase TBK1 and facilitates its oligomerization. Enhances the phosphorylation of NF-kappa-B p65 subunit RELA by TBK1. Promotes TBK1-induced as well as TNF-alpha or PMA-induced activation of NF-kappa-B. Participates in IFNB promoter activation via TICAM1.[1] [2] [3]
References
- ↑ Fujita F, Taniguchi Y, Kato T, Narita Y, Furuya A, Ogawa T, Sakurai H, Joh T, Itoh M, Delhase M, Karin M, Nakanishi M. Identification of NAP1, a regulatory subunit of IkappaB kinase-related kinases that potentiates NF-kappaB signaling. Mol Cell Biol. 2003 Nov;23(21):7780-93. PMID:14560022
- ↑ Sasai M, Oshiumi H, Matsumoto M, Inoue N, Fujita F, Nakanishi M, Seya T. Cutting Edge: NF-kappaB-activating kinase-associated protein 1 participates in TLR3/Toll-IL-1 homology domain-containing adapter molecule-1-mediated IFN regulatory factor 3 activation. J Immunol. 2005 Jan 1;174(1):27-30. PMID:15611223
- ↑ Goncalves A, Burckstummer T, Dixit E, Scheicher R, Gorna MW, Karayel E, Sugar C, Stukalov A, Berg T, Kralovics R, Planyavsky M, Bennett KL, Colinge J, Superti-Furga G. Functional dissection of the TBK1 molecular network. PLoS One. 2011;6(9):e23971. doi: 10.1371/journal.pone.0023971. Epub 2011 Sep 8. PMID:21931631 doi:http://dx.doi.org/10.1371/journal.pone.0023971
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