Research ArticleBiochemistry

Kinetics of CXCL12 binding to atypical chemokine receptor 3 reveal a role for the receptor N terminus in chemokine binding

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Science Signaling  10 Sep 2019:
Vol. 12, Issue 598, eaaw3657
DOI: 10.1126/scisignal.aaw3657

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ACKR3 holds with a hug

Ligand-receptor interactions transduce signals intracellularly that induce cellular responses to the ligand. For the atypical chemokine receptor ACKR3, however, it instead binds and sequesters its ligands (chemokines) that it shares with other chemokine receptors, thereby limiting the amount of chemokine available to activate intracellular signaling. Gustavsson et al. discovered the role of the N terminus of ACKR3 in controlling its interaction with the chemokine CXCL12. Binding of the chemokine to the receptor was mediated through its N-terminal region as expected; however, the N terminus of ACKR3 then wrapped around regions of the chemokine to hold it more tightly. These findings have broad implications for understanding chemokine ligand-receptor interactions as well as both chemokine-specific cell biology and drug design.

Abstract

Chemokines bind to membrane-spanning chemokine receptors, which signal through G proteins and promote cell migration. However, atypical chemokine receptor 3 (ACKR3) does not appear to couple to G proteins, and instead of directly promoting cell migration, it regulates the extracellular concentration of chemokines that it shares with the G protein–coupled receptors (GPCRs) CXCR3 and CXCR4, thereby influencing the responses of these receptors. Understanding how these receptors bind their ligands is important for understanding these different processes. Here, we applied association and dissociation kinetic measurements coupled to β-arrestin recruitment assays to investigate ACKR3:chemokine interactions. Our results showed that CXCL12 binding is unusually slow and driven by the interplay between multiple binding epitopes. We also found that the amino terminus of the receptor played a key role in chemokine binding and activation by preventing chemokine dissociation. It was thought that chemokines initially bind receptors through interactions between the globular domain of the chemokine and the receptor amino terminus, which then guides the chemokine amino terminus into the transmembrane pocket of the receptor to initiate signaling. On the basis of our kinetic data, we propose an alternative mechanism in which the amino terminus of the chemokine initially forms interactions with the extracellular loops and transmembrane pocket of the receptor, which is followed by the receptor amino terminus wrapping around the core of the chemokine to prolong its residence time. These data provide insight into how ACKR3 competes and cooperates with canonical GPCRs in its function as a scavenger receptor.

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