THE INTERFERON-GAMMA RECEPTOR EXTRACELLULAR DOMAIN - NONIDENTICAL REQUIREMENTS FOR LIGAND-BINDING AND SIGNALING

The human interferon-gamma receptor (hIFN-gamma R) extracellular domai n interacts in a species-specific manner with both its ligand and an a ccessory factor encoded on human chromosome 21. Mutant interferon-gamm a receptors were constructed by homolog-scanning mutagenesis, replacin g segments of the human extracellular domain with the corresponding mu rine sequence. Replacement of hIFN-gamma R amino acids 1-100, 100-132, 134-183, or 183-245 abolished binding to human interferon-gamma (hIFN -gamma). However, replacement of hIFN-gamma R amino acids 134-209, 183 -209, 134-153, 153-167, or 167-183 or deletion of residues 156-165 aff ected hIFN-gamma binding only partially or not at all. Receptors that bound hIFN-gamma were tested for their ability to signal a functional response, induction of major histocompatibility complex class I antige n expression. Replacement of residues 134-209 greatly reduced the abil ity of the receptor to signal. This signaling defect could not be attr ibuted solely to a reduction in affinity for ligand and could not be l ocalized to any subregion.