Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1

Leukocyte migration, a hallmark of the inflammatory response, is stimulated by the interactions between chemokines, which are expressed in injured or infected tissues, and chemokine receptors, which are G protein-coupled receptors (GPCRs) expressed in the leukocyte plasma membrane. One mechanism for...

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Main Authors: Julie Sanchez, J. Robert Lane, Meritxell Canals, Martin J. Stone
Format: Article
Language:English
Published: MDPI AG 2019-05-01
Series:International Journal of Molecular Sciences
Subjects:
Online Access:https://www.mdpi.com/1422-0067/20/10/2417
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spelling doaj-e028bffb5a8a42e9ae00d5136ad708ed2020-11-25T01:18:01ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-05-012010241710.3390/ijms20102417ijms20102417Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1Julie Sanchez0J. Robert Lane1Meritxell Canals2Martin J. Stone3Infection and Immunity Program, Monash Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, AustraliaCentre for Membrane Proteins and Receptors, Nottingham University, Nottingham, NG7 2RD, UKCentre for Membrane Proteins and Receptors, Nottingham University, Nottingham, NG7 2RD, UKInfection and Immunity Program, Monash Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, AustraliaLeukocyte migration, a hallmark of the inflammatory response, is stimulated by the interactions between chemokines, which are expressed in injured or infected tissues, and chemokine receptors, which are G protein-coupled receptors (GPCRs) expressed in the leukocyte plasma membrane. One mechanism for the regulation of chemokine receptor signaling is biased agonism, the ability of different chemokine ligands to preferentially activate different intracellular signaling pathways via the same receptor. To identify features of chemokines that give rise to biased agonism, we studied the activation of the receptor CCR1 by the chemokines CCL7, CCL8, and CCL15(Δ26). We found that, compared to CCL15(Δ26), CCL7 and CCL8 exhibited biased agonism towards cAMP inhibition and away from β-Arrestin 2 recruitment. Moreover, N-terminal substitution of the CCL15(Δ26) N-terminus with that of CCL7 resulted in a chimera with similar biased agonism to CCL7. Similarly, N-terminal truncation of CCL15(Δ26) also resulted in signaling bias between cAMP inhibition and β-Arrestin 2 recruitment signals. These results show that the interactions of the chemokine N-terminal region with the receptor transmembrane region play a key role in selecting receptor conformations coupled to specific signaling pathways.https://www.mdpi.com/1422-0067/20/10/2417chemokinechemokine receptorchemokine receptor 1 (CCR1)G protein-coupled receptor (GPCR)bindingreceptor activationbiased agonism
collection DOAJ
language English
format Article
sources DOAJ
author Julie Sanchez
J. Robert Lane
Meritxell Canals
Martin J. Stone
spellingShingle Julie Sanchez
J. Robert Lane
Meritxell Canals
Martin J. Stone
Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1
International Journal of Molecular Sciences
chemokine
chemokine receptor
chemokine receptor 1 (CCR1)
G protein-coupled receptor (GPCR)
binding
receptor activation
biased agonism
author_facet Julie Sanchez
J. Robert Lane
Meritxell Canals
Martin J. Stone
author_sort Julie Sanchez
title Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1
title_short Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1
title_full Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1
title_fullStr Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1
title_full_unstemmed Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1
title_sort influence of chemokine n-terminal modification on biased agonism at the chemokine receptor ccr1
publisher MDPI AG
series International Journal of Molecular Sciences
issn 1422-0067
publishDate 2019-05-01
description Leukocyte migration, a hallmark of the inflammatory response, is stimulated by the interactions between chemokines, which are expressed in injured or infected tissues, and chemokine receptors, which are G protein-coupled receptors (GPCRs) expressed in the leukocyte plasma membrane. One mechanism for the regulation of chemokine receptor signaling is biased agonism, the ability of different chemokine ligands to preferentially activate different intracellular signaling pathways via the same receptor. To identify features of chemokines that give rise to biased agonism, we studied the activation of the receptor CCR1 by the chemokines CCL7, CCL8, and CCL15(Δ26). We found that, compared to CCL15(Δ26), CCL7 and CCL8 exhibited biased agonism towards cAMP inhibition and away from β-Arrestin 2 recruitment. Moreover, N-terminal substitution of the CCL15(Δ26) N-terminus with that of CCL7 resulted in a chimera with similar biased agonism to CCL7. Similarly, N-terminal truncation of CCL15(Δ26) also resulted in signaling bias between cAMP inhibition and β-Arrestin 2 recruitment signals. These results show that the interactions of the chemokine N-terminal region with the receptor transmembrane region play a key role in selecting receptor conformations coupled to specific signaling pathways.
topic chemokine
chemokine receptor
chemokine receptor 1 (CCR1)
G protein-coupled receptor (GPCR)
binding
receptor activation
biased agonism
url https://www.mdpi.com/1422-0067/20/10/2417
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