Research ArticleChemokine Signaling

Structural basis for chemokine recognition by a G protein–coupled receptor and implications for receptor activation

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Sci. Signal.  21 Mar 2017:
Vol. 10, Issue 471, eaah5756
DOI: 10.1126/scisignal.aah5756

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How receptors view monomers versus dimers

Chemokines are proteins that stimulate cell migration in processes such as development, immune responses, and metastasis. Monomeric, dimeric, and oligomeric forms of chemokines can engage their cognate G protein–coupled receptors. Both the G protein–dependent and β-arrestin–dependent signaling pathways downstream of chemokine receptors must be activated to induce cell migration. Previous studies showed that a locked dimeric form of CXCL12 (LD CXCL12) fails to activate β-arrestin–dependent signaling after binding to its receptor CXCR4. Ziarek et al. solved the NMR structure of CXCR4 bound to a locked monomeric form of CXCL12 (LM CXCL12). LM CXCL12 physically interacted with the receptor differently than did the dimeric chemokine, and it stimulated both CXCR4-dependent signaling pathways to induce migration. Analysis of a hybrid NMR- and x-ray–based structure provided insights into the conformational changes required for chemokine receptor signaling, which may aid in designing drugs to target the chemokine family.

Abstract

Chemokines orchestrate cell migration for development, immune surveillance, and disease by binding to cell surface heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs). The array of interactions between the nearly 50 chemokines and their 20 GPCR targets generates an extensive signaling network to which promiscuity and biased agonism add further complexity. The receptor CXCR4 recognizes both monomeric and dimeric forms of the chemokine CXCL12, which is a distinct example of ligand bias in the chemokine family. We demonstrated that a constitutively monomeric CXCL12 variant reproduced the G protein–dependent and β-arrestin–dependent responses that are associated with normal CXCR4 signaling and lead to cell migration. In addition, monomeric CXCL12 made specific contacts with CXCR4 that are not present in the structure of the receptor in complex with a dimeric form of CXCL12, a biased agonist that stimulates only G protein–dependent signaling. We produced an experimentally validated model of an agonist-bound chemokine receptor that merged a nuclear magnetic resonance–based structure of monomeric CXCL12 bound to the amino terminus of CXCR4 with a crystal structure of the transmembrane domains of CXCR4. The large CXCL12:CXCR4 protein-protein interface revealed by this structure identified previously uncharacterized functional interactions that fall outside of the classical “two-site model” for chemokine-receptor recognition. Our model suggests a mechanistic hypothesis for how interactions on the extracellular face of the receptor may stimulate the conformational changes required for chemokine receptor–mediated signal transduction.

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