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 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.
Chakera
Aron
A
Sir William Dunn School of Pathology, University of Oxford, South Parks Rd., Oxford OX1 3RE, UK.
Seeber
Ruth M
RM
John
Alison E
AE
Eidne
Karin A
KA
Greaves
David R
DR
D000818:Animals; D019390:Arrestins / Q000378:metabolism; D001665:Binding Sites; D065100:CCR5 Receptor Antagonists; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D002633:Chemotaxis; D019281:Dimerization; D004375:Duffy Blood-Group System / Q000737:chemistry* / Q000378:metabolism*; D004705:Endocytosis; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D000071557:beta-Arrestins
C473745:ACKR1 protein, human; D019390:Arrestins; D065100:CCR5 Receptor Antagonists; D004375:Duffy Blood-Group System; D008024:Ligands; D011956:Receptors, Cell Surface; D000071557:beta-Arrestins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D002118:Calcium