Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1

Abstract

Leukocyte migration, a hallmark of the inflammatory response, is stimulated by the interactions between chemokines, which are expressed in injured or infected tissues, and chemokine receptors, which are G protein-coupled receptors (GPCRs) expressed in the leukocyte plasma membrane. One mechanism for the regulation of chemokine receptor signaling is biased agonism, the ability of different chemokine ligands to preferentially activate different intracellular signaling pathways via the same receptor. To identify features of chemokines that give rise to biased agonism, we studied the activation of the receptor CCR1 by the chemokines CCL7, CCL8, and CCL15(Δ26). We found that, compared to CCL15(Δ26), CCL7 and CCL8 exhibited biased agonism towards cAMP inhibition and away from β-Arrestin 2 recruitment. Moreover, N-terminal substitution of the CCL15(Δ26) N-terminus with that of CCL7 resulted in a chimera with similar biased agonism to CCL7. Similarly, N-terminal truncation of CCL15(Δ26) also resulted in signaling bias between cAMP inhibition and β-Arrestin 2 recruitment signals. These results show that the interactions of the chemokine N-terminal region with the receptor transmembrane region play a key role in selecting receptor conformations coupled to specific signaling pathways.

Molecular insights into ligand recognition and activation of chemokine receptors CCR2 and CCR3

“…2a ). The ligand recognition mode observed in the CCL2–CCR2–G i complex was consistent with the classic “two-site” model, which involves two main interaction sites between chemokines and their receptors: (1) chemokine recognition site 1 (CRS1) is at the N-terminus of the receptor, which interacts with the globular cores of chemokines; (2) chemokine recognition site 2 (CRS2) is within the TMD pocket of receptors, where the N-termini of chemokines are bound 29 , 30 . At the CRS1, the N-terminus of CCR2 (residues 29 GAPCH 33 ) formed several hydrophobic and hydrogen bonds with the N-terminus, N-loop, and nearby β3 region of CCL2 (Fig.…”

Structural basis of chemokine and receptor interactions: Key regulators of leukocyte recruitment in inflammatory responses

“…Moreover, as detailed by Volkman and colleagues, 39 a variety of additional observations point to the need for further refinement of the mechanistic model. Possible factors to consider include: involvement of additional structural elements in the interactions; 21,[40][41][42] allosteric cooperativity between the two sites; 43,44 preferential interactions of chemokines with different parts of the same receptor; 24,45,46 "biased" stimulation of different intracellular signaling pathways by different chemokines at same receptor; [47][48][49][50][51] receptor activation by some CXC chemokine dimers; 11,52,53 receptor homo-or hetero-dimerization; 54 and the effects of receptor or chemokine post-translational modifications. 28,30,46,55 In summary, while the models shown in Figures 1(D) and 1(E) capture key features of chemokine-receptor interactions, the details will need to be further experimentally elaborated and may be specific to each chemokine-receptor pair.…”

Systematic Assessment of Chemokine Signaling at Chemokine Receptors CCR4, CCR7 and CCR10

“…Such differences are classified as biased agonism if the ligands differ in their relative efficiencies of signaling via two alternative pathways, e.g., G protein versus β-arrestin pathways, or pathways mediated by different G protein subtypes. Biased agonism has been reported for several chemokine receptors, including CCR1, CCR2, CCR4, CCR5, CCR7, CCR10, CXCR2 and CXCR3 [4][5][6][7][8][9]. Biased agonism is distinct from differences in intrinsic efficacy (or partial agonism), which applies to ligands that activate the same pathways but differ in the relative magnitude of the signaling outcomes.…”