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| | <StructureSection load='4i9x' size='340' side='right'caption='[[4i9x]], [[Resolution|resolution]] 2.10Å' scene=''> | | <StructureSection load='4i9x' size='340' side='right'caption='[[4i9x]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4i9x]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Hcmvm Hcmvm] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4I9X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4I9X FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4i9x]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Human_herpesvirus_5_strain_Merlin Human herpesvirus 5 strain Merlin]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4I9X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4I9X FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></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=4i9x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i9x OCA], [https://pdbe.org/4i9x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4i9x RCSB], [https://www.ebi.ac.uk/pdbsum/4i9x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4i9x 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=4i9x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i9x OCA], [http://pdbe.org/4i9x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4i9x RCSB], [http://www.ebi.ac.uk/pdbsum/4i9x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4i9x ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[http://www.uniprot.org/uniprot/TR10B_HUMAN TR10B_HUMAN]] Defects in TNFRSF10B may be a cause of head and neck squamous cell carcinomas (HNSCC) [MIM:[http://omim.org/entry/275355 275355]]; also known as squamous cell carcinoma of the head and neck. | |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/UL141_HCMVM UL141_HCMVM]] Evasion of NK cell killing. Blocks surface expression of PVR which is a ligand for NK cell-activating receptors. Binds human PVR in the endoplasmic reticulum and prevents its maturation and transport to the cell surface. Targets also the natural killer cell activating ligand PVRL2/Nectin-2 for proteasome-mediated degradation.<ref>PMID:20410314</ref> [[http://www.uniprot.org/uniprot/TR10B_HUMAN TR10B_HUMAN]] Receptor for the cytotoxic ligand TNFSF10/TRAIL. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. Promotes the activation of NF-kappa-B. Essential for ER stress-induced apoptosis.<ref>PMID:15322075</ref> | + | [https://www.uniprot.org/uniprot/UL141_HCMVM UL141_HCMVM] Evasion of NK cell killing. Blocks surface expression of PVR which is a ligand for NK cell-activating receptors. Binds human PVR in the endoplasmic reticulum and prevents its maturation and transport to the cell surface. Targets also the natural killer cell activating ligand PVRL2/Nectin-2 for proteasome-mediated degradation.<ref>PMID:20410314</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Tumor necrosis factor receptor|Tumor necrosis factor receptor]] | + | *[[TRAIL|TRAIL]] |
| | + | *[[Tumor necrosis factor receptor 3D structures|Tumor necrosis factor receptor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Hcmvm]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Human herpesvirus 5 strain Merlin]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Nemcovicova, I]] | + | [[Category: Nemcovicova I]] |
| - | [[Category: Zajonc, D M]] | + | [[Category: Zajonc DM]] |
| - | [[Category: Apoptosis]]
| + | |
| - | [[Category: Ig-like domain]]
| + | |
| Structural highlights
Function
UL141_HCMVM Evasion of NK cell killing. Blocks surface expression of PVR which is a ligand for NK cell-activating receptors. Binds human PVR in the endoplasmic reticulum and prevents its maturation and transport to the cell surface. Targets also the natural killer cell activating ligand PVRL2/Nectin-2 for proteasome-mediated degradation.[1]
Publication Abstract from PubMed
The TRAIL (TNF-related apoptosis inducing ligand) death receptors (DRs) of the tumor necrosis factor receptor superfamily (TNFRSF) can promote apoptosis and regulate antiviral immunity by maintaining immune homeostasis during infection. In turn, human cytomegalovirus (HCMV) expresses immunomodulatory proteins that down-regulate cell surface expression of TNFRSF members as well as poliovirus receptor-related proteins in an effort to inhibit host immune effector pathways that would lead to viral clearance. The UL141 glycoprotein of human cytomegalovirus inhibits host defenses by blocking cell surface expression of TRAIL DRs (by retention in ER) and poliovirus receptor CD155, a nectin-like Ig-fold molecule. Here we show that the immunomodulatory function of HCMV UL141 is associated with its ability to bind diverse proteins, while utilizing at least two distinct binding sites to selectively engage TRAIL DRs or CD155. Binding studies revealed high affinity interaction of UL141 with both TRAIL-R2 and CD155 and low affinity binding to TRAIL-R1. We determined the crystal structure of UL141 bound to TRAIL-R2 at 2.1 A resolution, which revealed that UL141 forms a homodimer that engages two TRAIL-R2 monomers 90 degrees apart to form a heterotetrameric complex. Our structural and biochemical data reveal that UL141 utilizes its Ig-domain to facilitate non-canonical death receptor interactions while UL141 partially mimics the binding site of TRAIL on TRAIL-R2, which we found to be distinct from that of CD155. Moreover, UL141 also binds to an additional surface patch on TRAIL-R2 that is distinct from the TRAIL binding site. Therefore, the breadth of UL141-mediated effects indicates that HCMV has evolved sophisticated strategies to evade the immune system by modulating multiple effector pathways.
Structure of Human Cytomegalovirus UL141 Binding to TRAIL-R2 Reveals Novel, Non-canonical Death Receptor Interactions.,Nemcovicova I, Benedict CA, Zajonc DM PLoS Pathog. 2013 Mar;9(3):e1003224. doi: 10.1371/journal.ppat.1003224. Epub 2013, Mar 21. PMID:23555243[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Prod'homme V, Sugrue DM, Stanton RJ, Nomoto A, Davies J, Rickards CR, Cochrane D, Moore M, Wilkinson GW, Tomasec P. Human cytomegalovirus UL141 promotes efficient downregulation of the natural killer cell activating ligand CD112. J Gen Virol. 2010 Aug;91(Pt 8):2034-9. doi: 10.1099/vir.0.021931-0. Epub 2010 Apr, 21. PMID:20410314 doi:http://dx.doi.org/10.1099/vir.0.021931-0
- ↑ Nemcovicova I, Benedict CA, Zajonc DM. Structure of Human Cytomegalovirus UL141 Binding to TRAIL-R2 Reveals Novel, Non-canonical Death Receptor Interactions. PLoS Pathog. 2013 Mar;9(3):e1003224. doi: 10.1371/journal.ppat.1003224. Epub 2013, Mar 21. PMID:23555243 doi:http://dx.doi.org/10.1371/journal.ppat.1003224
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