Comprehensive mapping of poxvirus vCCI chemokine-binding protein. Expanded range of ligand interactions and unusual dissociation kinetics.
In compiling a comprehensive map of the ligand binding capacity of elements within the chemokine system, we have determined the spectrum of chemokines capable of interacting with the poxvirus-encoded viral CC chemokine inhibitor, vCCI. More than 80 chemokines were tested in parallel for their ability to displace radiolabeled signature chemokines from vCCI. Of these chemokines, 26 showed potential high affinity interactions. These interactions revealed an expanded spectrum of binding capacity for vCCI to now include molecules such as human myeloid progenitor inhibitory factor-1 as ligands. In addition, high affinity viral protein-protein interactions were revealed. For example, binding between poxvirus vCCI and the herpesvirus vMIP-II from HHV8 occurs with IC(50) approximately 10-50 nm. Unusual dissociation kinetics were observed between certain chemokines and vCCI. Notably, many ligands displayed a precipitous displacement profile, suggesting marked positive cooperativity of binding. Finally, heterologous competition provided evidence for overlapping but distinct binding sites for the many chemokines that bind to vCCI. The determination of the binding fingerprint and unusual binding interactions of vCCI with a large number of chemokines suggest a finely honed evolutionary strategy of chemokine sequestration during viral infection.
Burns
Jennifer M
JM
Division of Discovery Biology and Molecular Pharmacology, ChemoCentryx, San Carlos, California 94070, USA.
Dairaghi
Daniel J
DJ
Deitz
Mary
M
Tsang
Monica
M
Schall
Thomas J
TJ
D001667:Binding, Competitive; D018925:Chemokines / Q000378:metabolism*; D003902:Detergents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000939:Epitopes; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D011212:Poxviridae / Q000737:chemistry*; D011485:Protein Binding; D014764:Viral Proteins / Q000737:chemistry*; D037521:Virulence Factors
C414049:CCI protein, Cowpox virus; D018925:Chemokines; D003902:Detergents; D000939:Epitopes; D008024:Ligands; D014764:Viral Proteins; D037521:Virulence Factors