Kinetic Analysis of the Early Signaling Steps of the Human Chemokine Receptor CXCR4

• DOI: 10.1124/mol.119.118448
• Publication Date: 2020-05-31T02:55:12Z
• Authors: Cristina Perpiñá-...; Ali Işbilir; Aurélien Zarca; Birgit Caspar; Laura E. Kilpatrick; Stephen J. Hill; Martine J. Smit; Martin J. Lohse; Carsten Hoffmann
• Keywords: CXC chemokine receptors; CXCL14

G protein–coupled receptors (GPCRs) are biologic switches that transduce extracellular stimuli into intracellular responses in the cell. Temporally resolving GPCR transduction pathways is key to understanding how cell signaling occurs. Here, we investigate kinetics and dynamics of activation early steps CXC chemokine receptor (CXCR) 4 response its natural ligands ligand (CXCL) 12 macrophage migration inhibitory factor (MIF), using Förster resonance energy transfer–based approaches. We show CXCR4 presents a multifaceted CXCL12, with (≈0.6 seconds) followed by rearrangement receptor/G protein complex (≈1 seconds), slower dimer (≈1.7 prolonged (≈4 seconds). In comparison, MIF distinctly modulates every step pathway, indicating distinct mechanisms reflecting different pharmacological properties these two ligands. Our study also indicates exhibits some degree ligand-independent activity, relevant feature for drug development. <h3>SIGNIFICANCE STATEMENT</h3> The 12/CXC axis represents well-established therapeutic target cancer treatment. demonstrate involves dynamic rearrangements kinetically embedded between receptor–G activation. alternative endogenous behaves opposite CXCL12 each assay studied does not lead This detailed may aid development more specific drugs against this target.