Structural basis of GM-CSF and IL-2 sequestration by the viral decoy receptor GIF

Jan Felix, Eaazhisai Kandiah, Steven De Munck, Yehudi Bloch, Gydo C.P. van Zundert, Kris Pauwels, Ann Dansercoer, Katka Novanska, Randy J. Read, Alexandre M.J.J. Bonvin, Bjorn Vergauwen, Kenneth Verstraete, Irina Gutsche and Savvas N. Savvides ()
Additional contact information
Jan Felix: Laboratory for Protein Biochemistry and Biomolecular Engineering, Ghent University
Eaazhisai Kandiah: University Grenoble Alpes, CNRS, CEA, IBS
Steven De Munck: Laboratory for Protein Biochemistry and Biomolecular Engineering, Ghent University
Yehudi Bloch: Laboratory for Protein Biochemistry and Biomolecular Engineering, Ghent University
Gydo C.P. van Zundert: Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University
Kris Pauwels: VIB Structural Biology Research Center, Vrije Universiteit Brussel, Pleinlaan 2
Ann Dansercoer: Laboratory for Protein Biochemistry and Biomolecular Engineering, Ghent University
Katka Novanska: Masaryk University & CEITEC
Randy J. Read: University of Cambridge School of Clinical Medicine, Cambridge Institute for Medical Research
Alexandre M.J.J. Bonvin: Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University
Bjorn Vergauwen: Laboratory for Protein Biochemistry and Biomolecular Engineering, Ghent University
Kenneth Verstraete: Laboratory for Protein Biochemistry and Biomolecular Engineering, Ghent University
Irina Gutsche: University Grenoble Alpes, CNRS, CEA, IBS
Savvas N. Savvides: Laboratory for Protein Biochemistry and Biomolecular Engineering, Ghent University

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Subversion of the host immune system by viruses is often mediated by molecular decoys that sequester host proteins pivotal to mounting effective immune responses. The widespread mammalian pathogen parapox Orf virus deploys GIF, a member of the poxvirus immune evasion superfamily, to antagonize GM-CSF (granulocyte macrophage colony-stimulating factor) and IL-2 (interleukin-2), two pleiotropic cytokines of the mammalian immune system. However, structural and mechanistic insights into the unprecedented functional duality of GIF have remained elusive. Here we reveal that GIF employs a dimeric binding platform that sequesters two copies of its target cytokines with high affinity and slow dissociation kinetics to yield distinct complexes featuring mutually exclusive interaction footprints. We illustrate how GIF serves as a competitive decoy receptor by leveraging binding hotspots underlying the cognate receptor interactions of GM-CSF and IL-2, without sharing any structural similarity with the cytokine receptors. Our findings contribute to the tracing of novel molecular mimicry mechanisms employed by pathogenic viruses.

Date: 2016
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DOI: 10.1038/ncomms13228

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