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Tick evasins (EVAs) bind either CC or CXC-chemokines by a poorly understood promiscuous or "one-to-many" mechanism to neutralize inflammation. Since EVAs potently inhibit inflammation in many pre-clinical models, highlighting their potential as biological therapeutics for inflammatory diseases, we sought to further unravel the CXC-chemokine-EVA interactions. Using yeast surface display, we identified and characterized 27 novel CXC-chemokine-binding evasins homologous to EVA3 and defined two functional classes. The first, which included EVA3, exclusively bound ELR+ CXC-chemokines, whereas the second class bound both ELR+ and ELR- CXC-chemokines, in several cases including C-X-C motif chemokine ligand 10 (CXCL10), but, surprisingly, not CXCL8. The X-ray crystal structure of EVA3 at a resolution of 1.79 Å revealed a single anti-parallel b-sheet with six conserved cysteine residues forming a disulfide-bonded knottin scaffold which creates a contiguous solvent-accessible surface. Swapping analyses identified distinct knottin scaffold segments necessary for different CXC-chemokine-binding activities, implying that differential ligand positioning, at least in part, plays a role in promiscuous binding. Swapping segments also transferred chemokine-binding activity, resulting in a hybrid EVA with dual CXCL10- and CXCL8-binding activities. The solvent-accessible surfaces of the knottin scaffold segments have distinctive shape and charge, which we suggest drives chemokine binding specificity. These studies provide structural and mechanistic insight into how CXC-chemokine-binding tick EVAs achieve class specificity but also engage in promiscuous binding.

Original publication




Journal article


J Biol Chem

Publication Date



chemokine, chemotaxis, crystal structure, evasin, host-pathogen interaction, immune response, inflammation, knottin, protein-protein interaction, tick