The Duffy Antigen/Receptor for Chemokines Exists in an Oligomeric Form in Living Cells and Functionally Antagonizes CCR5 Signaling through Hetero-Oligomerization
The Duffy antigen/receptor for chemokines (DARC) is an unusual chemokine receptor that binds a large number of inflammatory chemokines of both the CC and CXC families with nanomolar affinity, yet it lacks the ability to signal upon ligand binding. Using bioluminescent resonant energy transfer, we ha...
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| Veröffentlicht in: | Molecular pharmacology 2008-05, Vol.73 (5), p.1362-1370 |
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| container_title | Molecular pharmacology |
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| creator | Chakera, Aron Seeber, Ruth M John, Alison E Eidne, Karin A Greaves, David R |
| description | The Duffy antigen/receptor for chemokines (DARC) is an unusual chemokine receptor that binds a large number of inflammatory
chemokines of both the CC and CXC families with nanomolar affinity, yet it lacks the ability to signal upon ligand binding.
Using bioluminescent resonant energy transfer, we have demonstrated for the first time that DARC exists as a constitutive
homo-oligomer in living cells and furthermore that DARC hetero-oligomerizes with the CC chemokine receptor CCR5. DARC-CCR5
interaction impairs chemotaxis and calcium flux through CCR5, whereas internalization of CCR5 in response to ligand binding
remains unchanged. These results suggest a novel mechanism by which DARC could modulate inflammatory responses to chemokines
in vivo. |
| doi_str_mv | 10.1124/mol.107.040915 |
| format | Article |
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Using bioluminescent resonant energy transfer, we have demonstrated for the first time that DARC exists as a constitutive
homo-oligomer in living cells and furthermore that DARC hetero-oligomerizes with the CC chemokine receptor CCR5. DARC-CCR5
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chemokines of both the CC and CXC families with nanomolar affinity, yet it lacks the ability to signal upon ligand binding.
Using bioluminescent resonant energy transfer, we have demonstrated for the first time that DARC exists as a constitutive
homo-oligomer in living cells and furthermore that DARC hetero-oligomerizes with the CC chemokine receptor CCR5. DARC-CCR5
interaction impairs chemotaxis and calcium flux through CCR5, whereas internalization of CCR5 in response to ligand binding
remains unchanged. These results suggest a novel mechanism by which DARC could modulate inflammatory responses to chemokines
in vivo.</description><subject>Animals</subject><subject>Arrestins - metabolism</subject><subject>beta-Arrestins</subject><subject>Binding Sites</subject><subject>Calcium - metabolism</subject><subject>CCR5 Receptor Antagonists</subject><subject>Cell Line</subject><subject>Cell Survival</subject><subject>Chemotaxis</subject><subject>Dimerization</subject><subject>Duffy Blood-Group System - chemistry</subject><subject>Duffy Blood-Group System - metabolism</subject><subject>Endocytosis</subject><subject>Endothelial Cells - cytology</subject><subject>Endothelial Cells - metabolism</subject><subject>GTP-Binding Protein alpha Subunits, Gi-Go - metabolism</subject><subject>Humans</subject><subject>Ligands</subject><subject>Mice</subject><subject>Protein Binding</subject><subject>Protein Structure, Quaternary</subject><subject>Receptors, Cell Surface - chemistry</subject><subject>Receptors, Cell Surface - metabolism</subject><subject>Signal Transduction</subject><subject>Transfection</subject><issn>0026-895X</issn><issn>1521-0111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUFv1DAQhS0EotvClSPyiVu2YydO4mMVuhRppUqlSNwsr3eSGBJ7sZPC9t_wT-tlV_TIwbLlee8bjx8h7xgsGePF5eiHJYNqCQVIJl6QBROcZcAYe0kWALzMaim-nZHzGL8DsELU8JqcsZrnUDGxIH_ue6Qf57bd0ys32Q7d5R0a3E0-0DatpsfR_7AOI73-beMUqXVUO3o72M6PGKyhKx_Gw-3aPljX0QaHISbJlq5mZybrnR6Gv3TdeWcfE6lp7gT9YrtUOTimPvi56-kNThh89g_9qA_uN-RVq4eIb0_7Bfm6ur5vbrL17afPzdU6MwVnU8Y2Jbas3GiASvPcABZYy0pUqKXhUBi5bWtsQYq6rpBvUJZ5IUqEbYkStMkvyIcjdxf8zxnjpEYbTRpGO_RzVKVMH85L_l8hh1JCBXUSLo9CE3yMAVu1C3bUYa8YqEN6KqWXzpU6ppcM70_keTPi9ll-iuu5dW-7_pcNqHa9DqM2fvDdXlW5Eorl6Y1PnEKlhQ</recordid><startdate>20080501</startdate><enddate>20080501</enddate><creator>Chakera, Aron</creator><creator>Seeber, Ruth M</creator><creator>John, Alison E</creator><creator>Eidne, Karin A</creator><creator>Greaves, David R</creator><general>American Society for Pharmacology and Experimental Therapeutics</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20080501</creationdate><title>The Duffy Antigen/Receptor for Chemokines Exists in an Oligomeric Form in Living Cells and Functionally Antagonizes CCR5 Signaling through Hetero-Oligomerization</title><author>Chakera, Aron ; 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chemokines of both the CC and CXC families with nanomolar affinity, yet it lacks the ability to signal upon ligand binding.
Using bioluminescent resonant energy transfer, we have demonstrated for the first time that DARC exists as a constitutive
homo-oligomer in living cells and furthermore that DARC hetero-oligomerizes with the CC chemokine receptor CCR5. DARC-CCR5
interaction impairs chemotaxis and calcium flux through CCR5, whereas internalization of CCR5 in response to ligand binding
remains unchanged. These results suggest a novel mechanism by which DARC could modulate inflammatory responses to chemokines
in vivo.</abstract><cop>United States</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>18230715</pmid><doi>10.1124/mol.107.040915</doi><tpages>9</tpages></addata></record> |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | Animals Arrestins - metabolism beta-Arrestins Binding Sites Calcium - metabolism CCR5 Receptor Antagonists Cell Line Cell Survival Chemotaxis Dimerization Duffy Blood-Group System - chemistry Duffy Blood-Group System - metabolism Endocytosis Endothelial Cells - cytology Endothelial Cells - metabolism GTP-Binding Protein alpha Subunits, Gi-Go - metabolism Humans Ligands Mice Protein Binding Protein Structure, Quaternary Receptors, Cell Surface - chemistry Receptors, Cell Surface - metabolism Signal Transduction Transfection |
| title | The Duffy Antigen/Receptor for Chemokines Exists in an Oligomeric Form in Living Cells and Functionally Antagonizes CCR5 Signaling through Hetero-Oligomerization |
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