Article (Scientific journals)
Mutational analysis of the extracellular disulphide bridges of the atypical chemokine receptor ACKR3/CXCR7 uncovers multiple binding and activation modes for its chemokine and endogenous non-chemokine agonists
Szpakowska, Martyna; Meyrath, Max Marc Roger; Reynders, Nathan et al.
2018In Biochemical Pharmacology, 153, p. 299-309
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Keywords :
ACKR3; CXCR4; chemokine receptor; CXCL12; disulfide bridge
Abstract :
[en] The atypical chemokine receptor ACKR3/CXCR7 plays crucial roles in numerous physiological processes but also in viral infection and cancer. ACKR3 shows strong propensity for activation and, unlike classical chemokine receptors, can respond to chemokines from both the CXC and CC families as well as to the endogenous peptides BAM22 and adrenomedullin. Moreover, despite belonging to the G protein coupled receptor family, its function appears to be mainly dependent on β-arrestin. ACKR3 has also been shown to continuously cycle between the plasma membrane and the endosomal compartments, suggesting a possible role as a scavenging receptor. So far, the molecular basis accounting for these atypical binding and signalling properties remains elusive. Noteworthy, ACKR3 extracellular domains bear three disulphide bridges. Two of them lie on top of the two main binding subpockets and are conserved among chemokine receptors, and one, specific to ACKR3, forms an intra-N terminus four-residue-loop of so far unknown function. Here, by mutational and functional studies, we examined the impact of the different disulphide bridges for ACKR3 folding, ligand binding and activation. We showed that, in contrast to most classical chemokine receptors, none of the extracellular disulphide bridges was essential for ACKR3 function. However, the disruption of the unique ACKR3 N-terminal loop drastically reduced the binding of CC chemokines whereas it only had a mild impact on CXC chemokine binding. Mutagenesis also uncovered that chemokine and endogenous non-chemokine ligands interact and activate ACKR3 according to distinct binding modes characterized by different transmembrane domain subpocket occupancy and N-terminal loop contribution, with BAM22 mimicking the binding mode of CC chemokine N terminus.
Research center :
Department of Infection and Immunity, Immuno-Pharmacology and Interactomics, Luxembourg Institute of Health
Structural Biology Brussels, Vrije Universiteit Brussel
Faculty of Science, Technology and Communication, University of Luxembourg
Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, GIGA B34, University of Liège,
VIB-VUB Center for Structural Biology
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Szpakowska, Martyna
Meyrath, Max Marc Roger 
Reynders, Nathan
Counson, Manuel
Hanson, Julien  ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Steyaert, Jan
Chevigné, Andy
Language :
English
Title :
Mutational analysis of the extracellular disulphide bridges of the atypical chemokine receptor ACKR3/CXCR7 uncovers multiple binding and activation modes for its chemokine and endogenous non-chemokine agonists
Publication date :
2018
Journal title :
Biochemical Pharmacology
ISSN :
0006-2952
eISSN :
1873-2968
Publisher :
Elsevier, Netherlands
Volume :
153
Pages :
299-309
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 13 June 2018

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