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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Felix, Jan 
Kandiah, Eaazhisai 
De Munck, Steven 
Bloch, Yehudi 
van Zundert, Gydo CP 

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.

Description

Keywords

Crystallography, X-Ray, Granulocyte-Macrophage Colony-Stimulating Factor, HEK293 Cells, Host-Pathogen Interactions, Humans, Interleukin-2, Models, Molecular, Multiprotein Complexes, Parapoxvirus, Poxviridae Infections, Protein Binding, Viral Proteins

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

7

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (209407/Z/17/Z)