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The playing field affects the players
Chemokines are small proteins that stimulate the directed migration of cells along a concentration gradient. In addition to binding to their G protein–coupled receptors, chemokines bind to heparan sulfate, a proteoglycan found in the extracellular matrix and on the surface of endothelial cells. Connell et al. found that although the γ isoform of the chemokine CXCL12 had a higher affinity for the receptor CXCR4 than did the α isoform, it was a poor stimulator of cellular migration. However, when CXCL12γ and heparan sulfate were presented together to cells, CXCR4 signaling was similar to that elicited by CXCL12α alone. Together, these data suggest that heparan sulfate acts to appropriately present some chemokines to their receptors rather than merely acting as a surface for their distribution. Thus, the design of drugs to target chemokine-receptor interactions should also take heparan sulfate binding into account.
Chemokines stimulate signals in cells by binding to G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors. These chemoattractant cytokines also interact with heparan sulfate (HS), which provides positional information within tissues in the form of haptotactic gradients along which cells can migrate directionally. To investigate the mechanism by which HS modulates chemokine functions, we used the CXC chemokine CXCL12, which exists in different isoforms that all signal through CXCR4 but have distinct HS-binding domains. In experiments with both cell-associated and solubilized CXCR4, we found that although CXCL12γ bound to CXCR4 with a higher affinity than did CXCL12α, CXCL12γ displayed reduced signaling and chemotactic activities. These properties were caused by the specific carboxyl-terminal region of CXCL12γ, which, by interacting with CXCR4 sulfotyrosines, mediated high-affinity, but nonproductive, binding to CXCR4. HS prevented CXCL12γ from interacting with the CXCR4 sulfotyrosines, thereby functionally presenting the chemokine to its receptor such that its activity was similar to that of CXCL12α. HS had no effects on the binding of CXCL12α to CXCR4 or its biological activity, suggesting that this polysaccharide controls CXCL12 in an isoform-specific manner. These data suggest that the HS-dependent regulation of chemokine functions extends beyond the simple process of immobilization and directly modulates receptor ligation and activation.