Hetero-oligomerization of chemokine receptors: diversity and relevance for function

The G protein-coupled receptor (GPCR) family of membrane receptors encompasses over 1000 members, representing the largest known receptor family, with a variety of structurally different ligands. GPCRs are favorite targets for drug development in numerous diseases. Chemokine receptors are an important GPCR sub-class and are known to play a crucial role in the regulation of multiple physiological and various pathophysiological processes, including inflammation, atherosclerosis, cancer, and viral infections. Chemokine receptor activation is controlled by some 50 chemokine ligands which often act in a redundant and overlapping manner, enabling for a complex regulatory system together controlling and fine-tuning the specificity and spatio-temporal properties of the response. Recent findings have indicated that additionally the organization of chemokine receptors on the cell surface could be critical for driving their biological effects. In fact, chemokine receptors have increasingly been found to organize into homo- or hetero-oligomeric complexes, in part in a ligand-inducible manner, resulting in complex networks and crosstalk with other orthogonal signaling complexes. There has even been evidence for heterologous complex formation between chemokine receptors and non-chemokine receptor G protein-coupled receptors (GPCRs), and even non-GPCRs. However, the functional consequences of this kind of oligomerization have remained poorly understood, even for the chemokine receptor homo-oligomers. Yet, there is growing evidence that targeting homo- and/or hetero-oligomerization of chemokine receptors might be beneficial for the development of novel and specific therapeutics. In the present article, we highlight the multi-faceted complexity of chemokine receptor structures with a focus on their hetero-oligomerization properties.