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Structural characterization of anti-CCL5 activity of the tick salivary protein Evasin-4

DOI: 10.1074/jbc.RA120.013891 DOI Help

Authors: Stepan S. Denisov (Maastricht University) , Mercedes Ramirez-Escudero (Utrecht University) , Alexandra C. A. Heinzmann (Maastricht University) , Johannes H. Ippel (Maastricht University) , Philip E. Dawson (The Scripps Research Institute) , Rory R. Koenen (Maastricht University) , Tilman M. Hackeng (Maastricht University) , Bert J. C. Janssen (Utrecht University) , Ingrid Dijkgraaf (Maastricht University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry

State: Published (Approved)
Published: August 2020
Diamond Proposal Number(s): 19800 , 1993

Abstract: Ticks, as blood sucking parasites, have developed a complex strategy to evade and suppress host immune responses during feeding. The crucial part of this strategy is expression of a broad family of salivary proteins, called Evasins, to neutralize chemokines responsible for cell trafficking and recruitment. However, structural information about Evasins is still scarce and little is known about the structural determinants of their binding mechanism to chemokines. Here, we studied the structurally uncharacterized Evasin-4, which neutralizes a broad range of CC-motif chemokines, including the chemokine CC-motif ligand 5 (CCL5) involved in atherogenesis. Crystal structures of Evasin-4 and E66S CCL5—an obligatory dimeric variant of CCL5—were determined to a resolution of 1.3-1.8 Å. The Evasin-4 crystal structure revealed an L-shaped architecture formed by an N- and C-terminal subdomain consisting of eight β-strands and an α-helix that adopts a substantially different position compared to closely related Evasin-1. Further investigation into E66S CCL5/Evasin-4 complex formation with NMR spectroscopy showed that residues of the N-terminus are involved in binding to CCL5. The peptide derived from the N-terminal region of Evasin-4 possessed nM affinity to CCL5 and inhibited CCL5 activity in monocyte migration assays. This suggests that Evasin-4 derivatives could be used as starting point for the development of anti-inflammatory drugs.

Journal Keywords: Ticks; parasite; protein structure; protein-protein interaction; immunosuppressor; chemokine; X-ray crystallography; nuclear magnetic resonance (NMR)

Diamond Keywords: Ticks

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I24-Microfocus Macromolecular Crystallography

Other Facilities: ID30-A3 and ID29 at ESRF

Added On: 19/08/2020 09:06

Discipline Tags:

Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)