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Publication Abstract from PubMed

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 A 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.

A knottin scaffold directs the CXC-chemokine-binding specificity of tick evasins.,Lee AW, Deruaz M, Lynch C, Davies G, Singh K, Alenazi Y, Eaton JRO, Kawamura A, Shaw J, Proudfoot AEI, Dias JM, Bhattacharya S J Biol Chem. 2019 Jun 5. pii: RA119.008817. doi: 10.1074/jbc.RA119.008817. PMID:31167786^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.