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Agonist-biased activity of chemokines and peptides derived from their N-terminus towards the atypical chemokine receptor CXCR7/ACKR3
Szpakowska, Martyna; Gauthier, Pierre-Arnaud; Derj, Anouar et al.
2014Chemotactic Cytokines – Gordon Research Conference - Positioning Cells in Immunity and Disease
 

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Abstract :
[en] CXCR7/ACKR3, the most recently identified chemokine receptor, binds two endogenous chemokines, CXCL12 and CXCL11, which are also recognized by CXCR4 and CXCR3, respectively. Unlike the conventional chemokine receptors that signal via G proteins, CXCR7 activates beta-arrestin-dependent pathways. CXCR7 plays a crucial role in many physiological and pathological processes but the exact molecular basis for its ligand recognition and activation remains poorly understood. In this study, we identified vCCL2, an antagonist broad spectrum viral chemokine, as the third high affinity ligand for CXCR7. In binding competition studies with labeled CXCL12, vCCL2 showed an IC50 = 33 nM and surprisingly acted as partial agonist in beta-arrestin recruitment assay (EC50 = 35 nM). Furthermore, we demonstrated that peptides corresponding to the flexible N-terminus and the N-loop of the three chemokines (CXCL12_1-17, CXCL11_1-17 and vCCL2_1-21) were alone able to bind CXCR7 and trigger beta-arrestin recruitment. Interestingly, in contrast to what we observed with full length chemokines, vCCL2_1-21 was more potent (IC50 = 0.62 uM) in binding CXCR7 than CXCL12_1-17 (IC50 = 6.5 uM) and CXCL11_1-17 (IC50 = 4 uM). This suggests that the three chemokines interact with CXCR7 using different determinants, with a higher contribution of the N-terminal fragment in vCCL2 binding. Further analyses with truncated or mutated N-terminal peptides showed that the N-loop residues is important only for vCCL2 binding and that deletion of the N-terminal lysine, P2G mutation and D-amino acid replacement in CXCL12-derived peptides do not change the properties of peptides from agonist to antagonist as observed for CXCR4. The identification of vCCL2 as the third ligand for CXCR7 with binding and activation behaviors different from CXCL12 and CXCL11 opens new possibilities to better understand the biology of this atypical receptor. Our results provide valuable information on CXCR7 interactions with its chemokine ligands, suggest that they display agonist-biased properties and identify their N-terminus as an important determinant of receptor activation.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Szpakowska, Martyna ;  Université de Liège - ULiège > Doct. sc. (bioch., biol. mol.&cell., bioinf.&mod.-Bologne)
Gauthier, Pierre-Arnaud;  Luxembourg Institute of Health
Derj, Anouar;  Université de Liège - ULiège
Counson, Manuel;  Luxembourg Institute of Health
Seguin-Devaux, Carole;  Luxembourg Institute of Health
Chevigné, Andy;  Luxembourg Institute of Health
Language :
English
Title :
Agonist-biased activity of chemokines and peptides derived from their N-terminus towards the atypical chemokine receptor CXCR7/ACKR3
Publication date :
July 2014
Event name :
Chemotactic Cytokines – Gordon Research Conference - Positioning Cells in Immunity and Disease
Event place :
Mount Snow (VT), United States
Event date :
27-07-2014 to 01-08-2014
Audience :
International
Available on ORBi :
since 11 June 2015

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