The structure and activity of a monomeric interferon-gamma:alpha-chain receptor signaling complex.
BACKGROUND
Interferon-gamma (IFN-gamma) is a homodimeric cytokine that exerts its various activities by inducing the aggregation of two different receptors. The alpha chain receptor (IFN-gammaRalpha) is a high affinity receptor that binds to IFN-gamma in a symmetric bivalent manner to form a stable, intermediate 1:2 complex. This intermediate forms a binding template for the subsequent binding of two copies of the second receptor, beta chain receptor (IFN-gammaRbeta), producing the active 1:2:2 signaling complex.


RESULTS
A single chain monovalent variant of IFN-gamma (scIFN-gamma) was constructed and complexed to one copy of the extracellular domain (ECD) of IFN-gammaRalpha. The structure of this 1:1 complex was determined and the hormone-receptor interface shown to be characterized by a number of hydrophilic interactions mediated by several highly ordered water networks. The scIFN-gamma interface consists of segments from each of the monomer chains of the homodimer. The principal hydrophobic contact of the receptor involves a tripeptide segment of the receptor having an unusual and high energy conformation. Despite containing only one binding site for IFN-gammaRalpha, the monovalent scIFN-gamma molecule has significant activity in antiviral biological assays.


CONCLUSIONS
ScIFN-gamma binds the ECD of IFN-gammaRalpha through a highly hydrated interface with an important set of hormone-receptor contacts mediated through structured waters. Although the interface is highly hydrated, it supports tight binding and has a considerable degree of specificity. The biological activity of scIFN-gamma confirms that the scIFN-gamma:IFN-gammaRalpha complex represents a productive intermediate and that it can effectively recruit the other required component, IFN-gammaRbeta, to signal based on the 1:1:1 complex.
Graduate Group in Biophysics, University of California, 94000, San Francisco, CA, USA.
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M
Randal
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Kossiakoff
D000998:Antiviral Agents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D007371:Interferon-gamma / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D017471:Receptors, Interferon / Q000737:chemistry*; D015398:Signal Transduction; D012997:Solvents; D000096743:Interferon gamma Receptor
D000998:Antiviral Agents; D007371:Interferon-gamma; D017471:Receptors, Interferon; D012997:Solvents; D000096743:Interferon gamma Receptor