Journal: Nat Commun / Year: 2016 Title: Structural basis of GM-CSF and IL-2 sequestration by the viral decoy receptor GIF. Authors: 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 ...Authors: 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 / Savvas N Savvides / 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 ...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.
History
Deposition
Jul 18, 2016
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Header (metadata) release
Oct 12, 2016
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Map release
Aug 2, 2017
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Update
Aug 2, 2017
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Current status
Aug 2, 2017
Processing site: PDBe / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Type: NEGATIVE / Material: Uranyl acetate Details: Negatively stained EM specimens were prepared using a carbon-sandwich technique and 2% (w/v) uranyl-acetate stain.
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Electron microscopy
Microscope
JEOL 1200EXII
Image recording
Film or detector model: KODAK SO-163 FILM / Average electron dose: 10.0 e/Å2
Electron beam
Acceleration voltage: 100 kV / Electron source: LAB6
Electron optics
Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.0 mm / Nominal magnification: 40000
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Image processing
Startup model
Type of model: INSILICO MODEL / In silico model: Ab-inition 3D reconstruction using VIPER
Final reconstruction
Applied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 17.0 Å / Resolution method: FSC 0.5 CUT-OFF / Number images used: 24324
Initial angle assignment
Type: PROJECTION MATCHING
Final angle assignment
Type: PROJECTION MATCHING
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Atomic model buiding 1
Refinement
Protocol: RIGID BODY FIT
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