classical and atypical chemokine receptors, member of the class A family of seven-transmembrane G protein-coupled receptors
Chemokines are principal regulators for leukocyte trafficking, recruitment, and activation. Chemokine family membership is defined on the basis of sequence homology and on the presence of variations on a conserved cysteine motif, which allows the family to further divide into four subfamilies (CC, CXC, XC, and CX3C). Chemokines interact with seven-transmembrane receptors which are typically coupled to G protein for signaling. Currently, there are ten known receptors for CC chemokines, seven for CXC chemokines, and single receptors for the XC and CX3C chemokines. In addition to these classical chemokine receptors, there exists a subfamily of atypical chemokine receptors (ACKRs) that are unable to couple to G-proteins and, instead, they preferentially mediate beta-arrestin dependent processes, such as receptor internalization, after ligand binding. The classical chemokine receptors contain a conserved DRYLAIV motif in the second intracellular loop, which is required for G-protein coupling. However, the ACKRs lack this conserved motif and fail to couple to G-proteins and induce classical GPCR signaling. Five receptors have been identified for the ACKR family, including CC-chemokine receptors like 1 and 2 (CCRL1 and CCRL2), CXCR7, Duffy antigen receptor for chemokine (DARC), and D6. Both ACKR1 (DARC) and ACKR3 (CXCR7) show low sequence homology to the classic chemokine receptors.