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| | ==Complex of high-affinity SIRP alpha variant FD6 with CD47== | | ==Complex of high-affinity SIRP alpha variant FD6 with CD47== |
| - | <StructureSection load='4kjy' size='340' side='right' caption='[[4kjy]], [[Resolution|resolution]] 1.93Å' scene=''> | + | <StructureSection load='4kjy' size='340' side='right'caption='[[4kjy]], [[Resolution|resolution]] 1.93Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4kjy]] 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=4KJY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KJY FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4kjy]] 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=4KJY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KJY FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.93Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CD47, MER6 ([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=4kjy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kjy OCA], [https://pdbe.org/4kjy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4kjy RCSB], [https://www.ebi.ac.uk/pdbsum/4kjy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4kjy 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=4kjy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kjy OCA], [http://pdbe.org/4kjy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4kjy RCSB], [http://www.ebi.ac.uk/pdbsum/4kjy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4kjy ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CD47_HUMAN CD47_HUMAN]] Has a role in both cell adhesion by acting as an adhesion receptor for THBS1 on platelets, and in the modulation of integrins. Plays an important role in memory formation and synaptic plasticity in the hippocampus (By similarity). Receptor for SIRPA, binding to which prevents maturation of immature dendritic cells and inhibits cytokine production by mature dendritic cells. Interaction with SIRPG mediates cell-cell adhesion, enhances superantigen-dependent T-cell-mediated proliferation and costimulates T-cell activation. May play a role in membrane transport and/or integrin dependent signal transduction. May prevent premature elimination of red blood cells. May be involved in membrane permeability changes induced following virus infection.<ref>PMID:7691831</ref> <ref>PMID:11509594</ref> <ref>PMID:15383453</ref> | + | [https://www.uniprot.org/uniprot/CD47_HUMAN CD47_HUMAN] Has a role in both cell adhesion by acting as an adhesion receptor for THBS1 on platelets, and in the modulation of integrins. Plays an important role in memory formation and synaptic plasticity in the hippocampus (By similarity). Receptor for SIRPA, binding to which prevents maturation of immature dendritic cells and inhibits cytokine production by mature dendritic cells. Interaction with SIRPG mediates cell-cell adhesion, enhances superantigen-dependent T-cell-mediated proliferation and costimulates T-cell activation. May play a role in membrane transport and/or integrin dependent signal transduction. May prevent premature elimination of red blood cells. May be involved in membrane permeability changes induced following virus infection.<ref>PMID:7691831</ref> <ref>PMID:11509594</ref> <ref>PMID:15383453</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: Garcia, K C]] | + | [[Category: Large Structures]] |
| - | [[Category: Ho, C C.M]] | + | [[Category: Garcia KC]] |
| - | [[Category: Ozkan, E]] | + | [[Category: Ho CCM]] |
| - | [[Category: Ring, A M]] | + | [[Category: Ozkan E]] |
| - | [[Category: Immune regulation]] | + | [[Category: Ring AM]] |
| - | [[Category: Immune system]]
| + | |
| - | [[Category: Immunoglobulin fold]]
| + | |
| - | [[Category: N-linked glycosylation]]
| + | |
| - | [[Category: Plasma membrane]]
| + | |
| Structural highlights
Function
CD47_HUMAN Has a role in both cell adhesion by acting as an adhesion receptor for THBS1 on platelets, and in the modulation of integrins. Plays an important role in memory formation and synaptic plasticity in the hippocampus (By similarity). Receptor for SIRPA, binding to which prevents maturation of immature dendritic cells and inhibits cytokine production by mature dendritic cells. Interaction with SIRPG mediates cell-cell adhesion, enhances superantigen-dependent T-cell-mediated proliferation and costimulates T-cell activation. May play a role in membrane transport and/or integrin dependent signal transduction. May prevent premature elimination of red blood cells. May be involved in membrane permeability changes induced following virus infection.[1] [2] [3]
Publication Abstract from PubMed
CD47 is an antiphagocytic signal that cancer cells employ to inhibit macrophage-mediated destruction. Here, we modified the binding domain of human SIRPalpha, the receptor for CD47, for use as a CD47 antagonist. We engineered high-affinity SIRPalpha variants with about a 50,000-fold increased affinity for human CD47 relative to wild-type SIRPalpha. As high-affinity SIRPalpha monomers, they potently antagonized CD47 on cancer cells but did not induce macrophage phagocytosis on their own. Instead, they exhibited remarkable synergy with all tumor-specific monoclonal antibodies tested by increasing phagocytosis in vitro and enhancing antitumor responses in vivo. This "one-two punch" directs immune responses against tumor cells while lowering the threshold for macrophage activation, thereby providing a universal method for augmenting the efficacy of therapeutic anticancer antibodies.
Engineered SIRPalpha variants as immunotherapeutic adjuvants to anticancer antibodies.,Weiskopf K, Ring AM, Ho CC, Volkmer JP, Levin AM, Volkmer AK, Ozkan E, Fernhoff NB, van de Rijn M, Weissman IL, Garcia KC Science. 2013 Jul 5;341(6141):88-91. doi: 10.1126/science.1238856. Epub 2013 May , 30. PMID:23722425[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lindberg FP, Gresham HD, Schwarz E, Brown EJ. Molecular cloning of integrin-associated protein: an immunoglobulin family member with multiple membrane-spanning domains implicated in alpha v beta 3-dependent ligand binding. J Cell Biol. 1993 Oct;123(2):485-96. PMID:7691831
- ↑ Latour S, Tanaka H, Demeure C, Mateo V, Rubio M, Brown EJ, Maliszewski C, Lindberg FP, Oldenborg A, Ullrich A, Delespesse G, Sarfati M. Bidirectional negative regulation of human T and dendritic cells by CD47 and its cognate receptor signal-regulator protein-alpha: down-regulation of IL-12 responsiveness and inhibition of dendritic cell activation. J Immunol. 2001 Sep 1;167(5):2547-54. PMID:11509594
- ↑ Piccio L, Vermi W, Boles KS, Fuchs A, Strader CA, Facchetti F, Cella M, Colonna M. Adhesion of human T cells to antigen-presenting cells through SIRPbeta2-CD47 interaction costimulates T-cell proliferation. Blood. 2005 Mar 15;105(6):2421-7. Epub 2004 Sep 21. PMID:15383453 doi:10.1182/blood-2004-07-2823
- ↑ Weiskopf K, Ring AM, Ho CC, Volkmer JP, Levin AM, Volkmer AK, Ozkan E, Fernhoff NB, van de Rijn M, Weissman IL, Garcia KC. Engineered SIRPalpha variants as immunotherapeutic adjuvants to anticancer antibodies. Science. 2013 Jul 5;341(6141):88-91. doi: 10.1126/science.1238856. Epub 2013 May , 30. PMID:23722425 doi:10.1126/science.1238856
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