title: The gammaherpesvirus chemokine binding protein can inhibit the interaction of chemokines with glycosaminoglycans.
abstract: Chemokines are small glycosaminoglycan (GAG) binding proteins that direct the migration of leukocytes by signaling through G protein coupled receptors (GPCR). Many viruses encode proteins that disrupt chemokine responses. The murine gammaherpesvirus-68 gene M3 encodes a chemokine binding protein (vCKBP-3), which has no sequence similarity to chemokine receptors. Initial characterization of vCKBP-3 showed that it inhibits receptor binding and chemokine-induced calcium influx. The structural requirements for the chemokines CXCL8 and CCL2 to bind to vCKBP-3 have been determined. Both chemokines bind to vCKBP-3 via their N-loop, a site that can participate in GAG binding for some chemokines. We have investigated the effect of vCKBP-3 on the interaction of chemokines with GAGs. We found that vCKBP-3 can prevent a range of chemokines from binding to GAGs. Moreover, we also found that vCKBP-3 can displace chemokines from a heparin-coated surface. Together, these data imply that vCKBP-3 can inhibit chemokine activity at two distinct levels. First, it inhibits chemokines from binding to their GPCR. Second, it inhibits their GAG binding and disrupts pre-formed chemokine gradients. This dual ability of vCKBP-3 makes it a more effective inhibitor of chemokine activity.
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Louise M C
authors.initials: LM
authors.lastname: Webb
authors.forename: Vincent P
authors.initials: VP
authors.lastname: Smith
authors.forename: Antonio
authors.initials: A
authors.lastname: Alcami
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D018925:Chemokines / Q000737:chemistry / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D018142:Gammaherpesvirinae / Q000502:physiology*; D006493:Heparin / Q000378:metabolism*; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D014764:Viral Proteins / Q000494:pharmacology*
chemical_list: D018925:Chemokines; C118862:M3 protein, Murine gammaherpesvirus; D011994:Recombinant Proteins; D014764:Viral Proteins; D006493:Heparin