4FA8 : Multi-pronged modulation of cytokine signaling

  • Xiaolin He (Contributor)
  • Ann Hye Ryong Shim (Contributor)

Dataset

Description

Experimental Technique/Method:X-RAY DIFFRACTION
Resolution:2.2
Classification:Viral Protein/Cytokine
Release Date:2012-08-29
Deposition Date:2012-05-21
Revision Date:
Molecular Weight:122079.21
Macromolecule Type:Protein
Residue Count:1050
Atom Site Count:8234
DOI:10.2210/pdb4fa8/pdb

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.
Date made available2012
PublisherRCSB-PDB

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