Allosteric competitive inactivation of hematopoietic CSF-1 signaling by the viral decoy receptor BARF1.
Nat Struct Mol Biol. 2012-08-19; 19(9): 938-947
DOI: 10.1038/nsmb.2367
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1. Nat Struct Mol Biol. 2012 Sep;19(9):938-47. doi: 10.1038/nsmb.2367. Epub 2012 Aug
19.
Allosteric competitive inactivation of hematopoietic CSF-1 signaling by the viral
decoy receptor BARF1.
Elegheert J(1), Bracke N, Pouliot P, Gutsche I, Shkumatov AV, Tarbouriech N,
Verstraete K, Bekaert A, Burmeister WP, Svergun DI, Lambrecht BN, Vergauwen B,
Savvides SN.
Author information:
(1)Laboratory for Protein Biochemistry and Biomolecular Engineering, Department
of Biochemistry & Microbiology, Ghent University, Ghent, Belgium.
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.
DOI: 10.1038/nsmb.2367
PMID: 22902366 [Indexed for MEDLINE]