Identification of a conserved chemokine receptor motif that enables ligand discrimination

Extensive ligand-receptor promiscuity in the chemokine signaling system balances beneficial redundancy and specificity. However, this feature poses a major challenge to selectively modulate the system pharmacologically. Here, we identified a conserved cluster of three aromatic receptor residues that...

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Bibliographic Details
Published in:Science signaling 2022-03, Vol.15 (724), p.eabg7042-eabg7042
Main Authors: Larsen, Olav, van der Velden, Wijnand J C, Mavri, Maša, Schuermans, Sara, Rummel, Pia C, Karlshøj, Stefanie, Gustavsson, Martin, Proost, Paul, Våbenø, Jon, Rosenkilde, Mette M
Format: Article
Language:English
Subjects:
CC chemokine receptors
CCR1 protein
CCR2 protein
CCR5 protein
Cell migration
Chemokine receptors
Chemokines
Chemokines - metabolism
Drug development
Homeostasis
Immune system
Ligands
Monocyte chemoattractant protein 1
Protein Structure, Secondary
Receptors
Receptors, CCR5 - metabolism
Receptors, Chemokine - genetics
Receptors, Chemokine - metabolism
Signal Transduction
Signaling
Subgroups
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Summary:Extensive ligand-receptor promiscuity in the chemokine signaling system balances beneficial redundancy and specificity. However, this feature poses a major challenge to selectively modulate the system pharmacologically. Here, we identified a conserved cluster of three aromatic receptor residues that anchors the second extracellular loop (ECL2) to the top of receptor transmembrane helices (TM) 4 and 5 and enables recognition of both shared and specific characteristics of interacting chemokines. This cluster was essential for the activation of several chemokine receptors. Furthermore, characteristic motifs of the ß strand and 30s loop make the two main CC-chemokine subgroups-the macrophage inflammatory proteins (MIPs) and monocyte chemoattractant proteins (MCPs)-differentially dependent on this cluster in the promiscuous receptors CCR1, CCR2, and CCR5. The cluster additionally enabled CCR1 and CCR5 to discriminate between closely related MIPs based on the N terminus of the chemokine. G protein signaling and β-arrestin2 recruitment assays confirmed the importance of the conserved cluster in receptor discrimination of chemokine ligands. This extracellular site may facilitate the development of chemokine-related therapeutics.
ISSN:1945-0877
1937-9145
DOI:10.1126/scisignal.abg7042