4FA8

Multi-pronged modulation of cytokine signaling

Summary for 4FA8

• Entry DOI: 10.2210/pdb4fa8/pdb
• 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, ... (5 entities in total)
• Functional Keywords: immunoglobulin-like domains, 4-helix bundle fold, viral protein-cytokine complex, viral protein/cytokine
• Biological source: Human herpesvirus 4 (HHV-4); More
• Total number of polymer chains: 6
• Total formula weight: 121971.12

Authors

He, X.,Shim, A.H. (deposition date: 2012-05-21, release date: 2012-08-29, Last modification date: 2020-07-29)

Primary citation

Shim, A.H.,Chang, R.A.,Chen, X.,Longnecker, R.,He, X.
Multipronged attenuation of macrophage-colony stimulating factor signaling by Epstein-Barr virus BARF1.
Proc.Natl.Acad.Sci.USA, 109:12962-12967, 2012

PubMed Abstract: The ubiquitous EBV causes infectious mononucleosis and is associated with several types of cancers. The EBV genome encodes an early gene product, BARF1, which contributes to pathogenesis, potentially through growth-altering and immune-modulating activities, but the mechanisms for such activities are poorly understood. We have determined the crystal structure of BARF1 in complex with human macrophage-colony stimulating factor (M-CSF), a hematopoietic cytokine with pleiotropic functions in development and immune response. BARF1 and M-CSF form a high-affinity, stable, ring-like complex in both solution and the crystal, with a BARF1 hexameric ring surrounded by three M-CSF dimers in triangular array. The binding of BARF1 to M-CSF dramatically reduces but does not completely abolish M-CSF binding and signaling through its cognate receptor FMS. A three-pronged down-regulation mechanism is proposed to explain the biological effect of BARF1 on M-CSF:FMS signaling. These prongs entail control of the circulating and effective local M-CSF concentration, perturbation of the receptor-binding surface of M-CSF, and imposition of an unfavorable global orientation of the M-CSF dimer. Each prong may reduce M-CSF:FMS signaling to a limited extent but in combination may alter M-CSF:FMS signaling dramatically. The downregulating mechanism of BARF1 underlines a viral modulation strategy, and provides a basis for understanding EBV pathogenesis.

PubMed: 22826234
DOI: 10.1073/pnas.1205309109

Experimental method

X-RAY DIFFRACTION (2.2 Å)