The role of three domains in the biological activity of human interferon-alpha.
Earlier studies showed that minor differences in primary structure among the interferon-alpha (IFN-alpha) protein family are reflected in their potency in selected biological assays. These studies have been extended and results from assays of antiviral, growth inhibitory and 2',5'-oligoadenylate (2-5A) synthetase activities indicate that the various novel hybrid and analog species are differentially biologically active. Overall these observations suggest a correlation between predicted secondary structure characteristics, receptor binding affinity, and 2-5A synthetase, antiviral and growth inhibitory activities. Studies with a consensus IFN-alpha analog particularly implicated the region around residues 78 and 79 as influencing antiviral activity. Neutralization experiments with a monoclonal antibody directed against a conserved region from residues 113 to 149 indicated that although this region of the IFN-alpha molecule may be important for antiviral activity, altering residues at sites removed from this region may reduce the effectiveness of the neutralizing antibody. Receptor binding experiments suggested that no single site at either the amino or carboxyl terminus of IFN-alpha alone determines receptor affinity or biological activity: apparently three distinct domains along IFN-alpha are involved (10-35, 78-107, 123-166). Overall, the data indicate that the three sites contribute toward the active configuration of human IFN-alpha.
Fish
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EN
Department of Microbiology, University of Toronto, Canada.
Banerjee
K
K
Stebbing
N
N
D015088:2',5'-Oligoadenylate Synthetase / Q000032:analysis / Q000096:biosynthesis; D000595:Amino Acid Sequence; D002478:Cells, Cultured; D004790:Enzyme Induction; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D011237:Predictive Value of Tests; D011487:Protein Conformation; D011971:Receptors, Immunologic / Q000378:metabolism; D017471:Receptors, Interferon; D014407:Tumor Cells, Cultured
D006131:Growth Inhibitors; D007370:Interferon Type I; D011971:Receptors, Immunologic; D017471:Receptors, Interferon; D015088:2',5'-Oligoadenylate Synthetase