Stable conformation of an interferon-gamma receptor binding peptide in aqueous solution is required for interferon-gamma antagonist activity.
A peptide antagonist for mouse interferon-gamma (IFN-gamma) activity corresponding to the amino-terminal 39 amino acids of mouse IFN-gamma [MuIFN-gamma (1-39)] has been identified previously. In an analogous manner, we have assessed the ability of the corresponding peptide of human IFN-gamma [HuIFN-gamma (1-39)] to antagonize human IFN-gamma. HuIFN-gamma (1-39) has the ability to block the antiviral activity of human IFN-gamma in a functional assay. In receptor competition, the peptide can also block human IFN-gamma receptor binding. Surprisingly, the murine analog, MuIFN-gamma (1-39), possesses a 10-fold greater ability to block human IFN-gamma antiviral activity and receptor binding than HuIFN-gamma (1-39). Both peptides showed alpha-helical structure in water by circular dichroism, however MuIFN-gamma (1-39) possessed a greater amount of alpha-helix compared to HuIFN-gamma (1-39), suggesting a requirement for a stable secondary structure for optimal antagonist activity. In trifluoroethanol, a helix-stabilizing agent, both peptides showed relatively equal alpha-helices, suggesting that both sequences have an equal potential for helical structure. As IFN-gamma is species specific, the observation that MuIFN-gamma (1-39) can antagonize human IFN-gamma raises questions about the role of this region in species specificity. These studies provide insight into the structural requirements, both primary and secondary, for IFN-gamma receptor binding. In the future, this information, along with more detailed three-dimensional structural analyses of the peptides, could prove useful in the rational design of IFN-gamma agonists and antagonists.
Jarpe
M A
MA
Department of Microbiology and Cell Science, University of Florida, Gainesville 32611.
Johnson
H M
HM
D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation; D017471:Receptors, Interferon; D017386:Sequence Homology, Amino Acid; D014867:Water
D010455:Peptides; D017471:Receptors, Interferon; D014867:Water; D007371:Interferon-gamma