Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium.
Sci Signal. 2022 Mar 8;15(724):eabg7042. doi: 10.1126/scisignal.abg7042.
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.
趋化因子信号系统中的广泛配体-受体混杂性平衡了有益的冗余性和特异性。然而，这一特性给选择性地对该系统进行药理学调节带来了巨大的挑战。在这里，我们鉴定了趋化因子受体中三个芳香族残基的保守簇，该簇将第二细胞外环（ECL2）锚定在跨膜螺旋（TM）4 和 5 的顶部，并能识别相互作用的趋化因子的共享和特定特征。该簇对于几种趋化因子受体的激活至关重要。此外，β链和 30s 环的特征基序使得两个主要的 CC-趋化因子亚群——巨噬细胞炎症蛋白（MIPs）和单核细胞趋化蛋白（MCPs）——在混杂受体 CCR1、CCR2 和 CCR5 中对该簇的依赖性不同。该簇还使 CCR1 和 CCR5 能够根据趋化因子的 N 末端区分密切相关的 MIPs。G 蛋白信号和β-arrestin2 募集试验证实了该保守簇在受体对趋化因子配体的识别中的重要性。该细胞外位点可能有助于开发与趋化因子相关的治疗方法。
