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First published on January 29, 2008; DOI: 10.1124/mol.107.040915

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Karin A Eidne
David R Greaves
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Received for publication August 23, 2007.
Revised January 29, 2008.
Accepted for publication January 29, 2008.

The Duffy Antigen/Receptor for Chemokines (DARC) exists in an oligomeric form in living cells and functionally antagonises CCR5 signalling through hetero-oligomerization

Aron Chakera 1, Ruth M Seeber 2, Alison E John 1, Karin A Eidne 2, David R Greaves 1*

1 University of Oxford 2 The Western Australian Institute for Medical Research and Centre, University of Western Australia

* Address correspondence to: E-mail: david.greaves{at}path.ox.ac.uk

Abstract

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 lacks the ability to signal upon ligand binding. Using bioluminescent resonant energy transfer (BRET) 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, while 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.


Key words: Gi family, Sequestration/Internalization, Fluorescence techniques




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