G-Protein-Coupled Receptors: from Structural Insights to Functional Mechanisms

ACRs (atypical chemokine receptors) were initially referred to as ‘silent’ receptors on the basis of a lack of signalling and functional activities that are typically observed with conventional chemokine receptors. Although ACRs do not directly induce cell migration, they indirectly control leucocyte recruitment by shaping chemokine gradients in tissues through degradation, transcytosis or local concentration of their cognate ligands. Recent evidence also suggests that these biological activities are supported by G-proteinindependent, β-arrestin-dependent signalling events. In the present article, we review current knowledge on structural and signalling properties of ACRs that are changing our view on this entire class of receptors from silent to endogenous β-arrestin-biased signalling receptors. Introducing the ‘silent’ ACRs (atypical chemokine receptors) Chemokines regulate leucocyte migration through the activation of a distinct family of conventional 7TMRs (seven-transmembrane domain receptors) [1]. Signalling by chemokine receptors relies on a G-protein-dependent signalling module promoting cell migration, integrated with a β-arrestin-dependent signalling module that functionally uncouples G-proteins from the receptor and subsequently desensitizes and internalizes it via clathrin-coated pitsdependent endocytosis [2,3]. In recent years it has become increasingly evident that the role of β-arrestins is not limited to receptor desensitization and internalization; their function of adaptor proteins providing diversity and finetuning of signalling activities is emerging [4]. Interestingly, it has been reported that although most 7TMRs signal in a balanced fashion through the G-protein and β-arrestin modules [5,6], mutations in key residues have been shown to generate G-proteinor β-arrestin-biased receptors [4]. However, so far, β-arrestin-biased receptors have only been genetically engineered from balanced receptors by mutations in key residues involved in G-protein coupling, including the DRYLAIV motif in ICL (intracellular loop) 2 [7] and some highly conserved residues in TM (transmembrane) 2, 3 and 5 domains [8], whereas no natural cases of β-arrestin-biased receptors have been described. Emerging evidence suggesting candidates for such βarrestin-biased receptors are a set of chemokine receptors referred to as atypical or silent receptors, which are unable to