Structure of an Epitope in an Immunodominant Region of the Interferon-γ Molecule that Is Involved in Receptor Interaction

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Abstract
An amino-terminal immunodominant region of murine interferon-γ (IFN-γ) that may be involved in function is characterized using a neutralizing amino-terminal-specific monoclonal antibody (mAb) and synthetic peptides. Competition studies with peptide truncations determined that residues 3,4, and 5 of IFN-γ were required for binding to the mAb. These residues are predicted to participate in an amphipathic α-helix spanning residues 3–11 of IFN-γ. Conservative peptide analogs that maintain the amphipathicity of the α-helix of IFN–γ (1–20) retained the ability to block IFN-γ binding to mAb. Peptide analogs with substitutions that disrupted the amphipathicity of the α-helix lost their ability to block binding. The tyrosine at position 14 was required as its removal in carboxy-terminal truncations caused the loss of blocking ability. We conclude that the IFN-γ epitope for the neutralizing mAb involves residues 3–14, spanning 12 residues, and it appears that residues 3,4,5, and 14 are an important part of the epitope. Based on these characteristics and the observation that most continuous epitopes are reported to involve shorter regions of up to 8 residues, this epitope may be described as a linear discontinuous epitope that may require the amphipathic helix. The data presented here provide further insight to the structure of a site that is involved in receptor interaction.