3UEZ

Crystal structure of the human Colony-Stimulating Factor 1 (hCSF-1) cytokine in complex with the viral receptor BARF1

Summary for 3UEZ

• Entry DOI: 10.2210/pdb3uez/pdb
• Related: 1HMC 2CH8 3UF2 3UF5
• Descriptor: Secreted protein BARF1, Macrophage colony-stimulating factor 1, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: viral receptor, rtkiii, extracellular, cytokine receptor-cytokine complex, cytokine, four-helix bundle, glycoprotein, immunoglobulin domain, oncogene, receptor, cytokine/signaling, protein complex, cytokine receptor/cytokine
• Biological source: Human herpesvirus 4 (HHV-4); More
• Total number of polymer chains: 8
• Total formula weight: 167469.66

Authors

Elegheert, J.,Bracke, N.,Savvides, S.N. (deposition date: 2011-10-31, release date: 2012-08-22, Last modification date: 2024-10-30)

Primary citation

Elegheert, J.,Bracke, N.,Pouliot, P.,Gutsche, I.,Shkumatov, A.V.,Tarbouriech, N.,Verstraete, K.,Bekaert, A.,Burmeister, W.P.,Svergun, D.I.,Lambrecht, B.N.,Vergauwen, B.,Savvides, S.N.
Allosteric competitive inactivation of hematopoietic CSF-1 signaling by the viral decoy receptor BARF1
Nat.Struct.Mol.Biol., 19:938-947, 2012

PubMed Abstract: Hematopoietic human colony-stimulating factor 1 (hCSF-1) is essential for innate and adaptive immunity against viral and microbial infections and cancer. The human pathogen Epstein-Barr virus secretes the lytic-cycle protein BARF1 that neutralizes hCSF-1 to achieve immunomodulation. Here we show that BARF1 binds the dimer interface of hCSF-1 with picomolar affinity, away from the cognate receptor-binding site, to establish a long-lived complex featuring three hCSF-1 at the periphery of the BARF1 toroid. BARF1 locks dimeric hCSF-1 into an inactive conformation, rendering it unable to signal via its cognate receptor on human monocytes. This reveals a new functional role for hCSF-1 cooperativity in signaling. We propose a new viral strategy paradigm featuring an allosteric decoy receptor of the competitive type, which couples efficient sequestration and inactivation of the host growth factor to abrogate cooperative assembly of the cognate signaling complex.

PubMed: 22902366
DOI: 10.1038/nsmb.2367

Experimental method

X-RAY DIFFRACTION (3.414 Å)