Identification of a conserved chemokine receptor motif that enables ligand discrimination

• DOI: 10.1126/scisignal.abg7042
• Publication Date: 2022-03-08T18:54:37Z
• Authors: Olav Larsen; Wijnand J. C. van...; Maša Mavri; Sara Schuermans; Pia C. Rummel; Stefanie Karlshøj; Martin Gustavsson; Paul Proost; Jon Våbenø; Mette M. Rosenkilde
• Keywords: CCR1; CCL21; CCR2; CCL7; CC chemokine receptors; CCL13; XCL2

Extensive ligand-receptor promiscuity in the chemokine signaling system balances beneficial redundancy and specificity. However, this feature poses a major challenge to selectively modulate pharmacologically. Here, we identified conserved cluster of three aromatic receptor residues that anchors second extracellular loop (ECL2) top transmembrane helices (TM) 4 5 enables recognition both shared specific characteristics interacting chemokines. This was essential for activation several receptors. Furthermore, characteristic motifs ß 1 strand 30s make two main CC-chemokine subgroups—the macrophage inflammatory proteins (MIPs) monocyte chemoattractant (MCPs)—differentially dependent on promiscuous receptors CCR1, CCR2, CCR5. The additionally enabled CCR1 CCR5 discriminate between closely related MIPs based N terminus chemokine. G protein β-arrestin2 recruitment assays confirmed importance discrimination ligands. site may facilitate development chemokine-related therapeutics.