The structure and activity of a monomeric interferon-gamma:alpha-chain receptor signaling complex

Structure. 2001 Feb 7;9(2):155-63. doi: 10.1016/s0969-2126(01)00567-6.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antiviral Agents / chemistry*
  • Crystallography, X-Ray
  • Hydrogen Bonding
  • Interferon gamma Receptor
  • Interferon-gamma / chemistry*
  • Models, Molecular
  • Molecular Structure
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • Receptors, Interferon / chemistry*
  • Signal Transduction
  • Solvents

Substances

  • Antiviral Agents
  • Receptors, Interferon
  • Solvents
  • Interferon-gamma