TY - JOUR
T1 - Different contributions of chemokine N-terminal features attest to a different ligand binding mode and a bias towards activation of ACKR3/CXCR7 compared with CXCR4 and CXCR3
AU - Szpakowska, Martyna
AU - Nevins, Amanda M.
AU - Meyrath, Max
AU - Rhainds, David
AU - D'huys, Thomas
AU - Guité-Vinet, François
AU - Dupuis, Nadine
AU - Gauthier, Pierre Arnaud
AU - Counson, Manuel
AU - Kleist, Andrew
AU - St-Onge, Geneviève
AU - Hanson, Julien
AU - Schols, Dominique
AU - Volkman, Brian F.
AU - Heveker, Nikolaus
AU - Chevigné, Andy
N1 - Funding Information:
This study was supported by the Luxembourg Institute of Health (MESR) grants 20160116 and 20170113, Fonds De La Recherche Scientifique - FNRS - T?l?vie grants 7456814 and 7461515, the programme financing of the KU Leuven (PF/10/018), F.R.S.-FNRS incentive grant for scientific research (MIS-F.4510.14) as well as National Institutes of Health (NIH) grants F30CA196040 (A.K.) and R01 AI058072 (B.F.V.) and grant MOP123421 from the Canadian Institutes of Health Research (CIHR) (N.H.). M.S., M.M. and P.-A.G. are the Luxembourg National Research Fund (?Fonds National de la Recherche - Aides ? la Formation-Recherche?, FNR-AFR) PhD fellows (grants AFR-3004509, AFR-11274579 and AFR-5907281) and INTER/FWO/15/10358798. J.H. is a ?Fonds de la Recherche Scientifique? (Fonds de la Recherche Scientifique - FNRS, Belgium) research associate. N.D. is a ?Fonds pour la Recherche dans l'Industrie et l'Agriculture (FRIA)? research fellow. A.K. is a member of the NIH-supported (T32 GM080202) Medical Scientist Training Program at MCW. F.G.V. acknowledges a CIHR scholarship. The authors wish to thank Mathias Plourde in the Heveker Lab for his contributions to the BRET measurements.
Funding Information:
This study was supported by the Luxembourg Institute of Health (MESR) grants 20160116 and 20170113, Fonds De La Recherche Scientifique - FNRS - Télévie grants 7456814 and 7461515, the programme financing of the KU Leuven (PF/10/018), F.R.S.-FNRS incentive grant for scientific research (MIS-F.4510.14) as well as National Institutes of Health (NIH) grants F30CA196040 (A.K.) and R01 AI058072 (B.F.V.) and grant MOP123421 from the Canadian Institutes of Health Research (CIHR) (N.H.). M.S., M.M. and P.-A.G. are the Luxembourg National Research Fund (‘Fonds National de la Recherche - Aides à la Formation-Recherche’, FNR-AFR) PhD fellows (grants AFR-3004509, AFR-11274579 and AFR-5907281) and INTER/FWO/15/10358798. J.H. is a ‘Fonds de la Recherche Scientifique’ (Fonds de la Recherche Scientifique - FNRS, Belgium) research associate. N.D. is a ‘Fonds pour la Recherche dans l’Industrie et l’Agriculture (FRIA)’ research fellow. A.K. is a member of the NIH-supported (T32 GM080202) Medical Scientist Training Program at MCW. F.G.V. acknowledges a CIHR scholarship. The authors wish to thank Mathias Plourde in the Heveker Lab for his contributions to the BRET measurements.
Publisher Copyright:
© 2017 The British Pharmacological Society
PY - 2018/5
Y1 - 2018/5
N2 - Background and Purpose: Chemokines and their receptors form an intricate interaction and signalling network that plays critical roles in various physiological and pathological cellular processes. The high promiscuity and apparent redundancy of this network makes probing individual chemokine/receptor interactions and functional effects, as well as targeting individual receptor axes for therapeutic applications, challenging. Despite poor sequence identity, the N-terminal regions of chemokines, which play a key role in their activity and selectivity, contain several conserved features. Thus far little is known regarding the molecular basis of their interactions with typical and atypical chemokine receptors or the conservation of their contributions across chemokine-receptor pairs. Experimental Approach: We used a broad panel of chemokine variants and modified peptides derived from the N-terminal region of chemokines CXCL12, CXCL11 and vCCL2, to compare the contributions of various features to binding and activation of their shared receptors, the two typical, canonical G protein-signalling receptors, CXCR4 and CXCR3, as well as the atypical scavenger receptor CXCR7/ACKR3, which shows exclusively arrestin-dependent activity. Key Results: We provide molecular insights into the plasticity of the ligand-binding pockets of these receptors, their chemokine binding modes and their activation mechanisms. Although the chemokine N-terminal region is a critical determinant, neither the most proximal residues nor the N-loop are essential for binding and activation of ACKR3, as distinct from binding and activation of CXCR4 and CXCR3. Conclusion and Implications: These results suggest a different interaction mechanism between this atypical receptor and its ligands and illustrate its strong propensity to activation.
AB - Background and Purpose: Chemokines and their receptors form an intricate interaction and signalling network that plays critical roles in various physiological and pathological cellular processes. The high promiscuity and apparent redundancy of this network makes probing individual chemokine/receptor interactions and functional effects, as well as targeting individual receptor axes for therapeutic applications, challenging. Despite poor sequence identity, the N-terminal regions of chemokines, which play a key role in their activity and selectivity, contain several conserved features. Thus far little is known regarding the molecular basis of their interactions with typical and atypical chemokine receptors or the conservation of their contributions across chemokine-receptor pairs. Experimental Approach: We used a broad panel of chemokine variants and modified peptides derived from the N-terminal region of chemokines CXCL12, CXCL11 and vCCL2, to compare the contributions of various features to binding and activation of their shared receptors, the two typical, canonical G protein-signalling receptors, CXCR4 and CXCR3, as well as the atypical scavenger receptor CXCR7/ACKR3, which shows exclusively arrestin-dependent activity. Key Results: We provide molecular insights into the plasticity of the ligand-binding pockets of these receptors, their chemokine binding modes and their activation mechanisms. Although the chemokine N-terminal region is a critical determinant, neither the most proximal residues nor the N-loop are essential for binding and activation of ACKR3, as distinct from binding and activation of CXCR4 and CXCR3. Conclusion and Implications: These results suggest a different interaction mechanism between this atypical receptor and its ligands and illustrate its strong propensity to activation.
UR - http://www.scopus.com/inward/record.url?scp=85044208341&partnerID=8YFLogxK
U2 - 10.1111/bph.14132
DO - 10.1111/bph.14132
M3 - Article
C2 - 29272550
AN - SCOPUS:85044208341
SN - 0007-1188
VL - 175
SP - 1419
EP - 1438
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 9
ER -