Shifting CCR7 towards its monomeric form augments CCL19 binding and uptake

The chemokine receptor CCR7, together with its ligands, is responsible for the migration and positioning of adaptive immune cells, and hence critical for launching adaptive immune responses. CCR7 is also induced on certain cancer cells and contribute to metastasis formation. Thus, CCR7 expression and signaling must be tightly regulated for proper function. CCR7, as many other members of the G-protein coupled receptor superfamily, can form homo-dimers and oligomers. Notably, danger signals associated with pathogen encounter promote oligomerization of CCR7 and is considered as one layer of regulating its function. Here, we assessed dimerization of human CCR7 and several single point mutations by split-luciferase complementation assays. We demonstrate that dimerization-defective CCR7 mutants can be transported to the cell surface and elicit normal chemokine-driven G-protein activation. By contrast, we discovered that CCR7 mutants, whose expression are shifted towards monomers significantly augment their capacities to bind and internalize fluorescently labelled CCL19. Modeling receptor suggests that dimerization-defective CCR7 mutants render the extracellular loops more flexible and less structured, such that the chemokine recognition site located in the binding pocket might becomes more accessible to its ligand. Overall, we provide new insights into how the dimerization state of CCR7 affects CCL19 binding and receptor trafficking.