Structure-function relationships in the interferon-tau (IFN-tau). Changes in receptor binding and in antiviral and antiproliferative activities resulting from site-directed mutagenesis performed near the carboxyl terminus.
The interferons-tau (IFN-tau) are Type I IFN, 172 amino acids in length, which are produced by the trophoblast of ruminant ungulate species and whose only known function is in triggering maternal responses to pregnancy. These IFN have the normal antiviral and antiproliferative activities exhibited by other Type I IFN, such as IFN-alpha and -beta, and are predicted to have similar structures based on five alpha-helices (A-E). A series of ovine IFN-tau variants was prepared with alterations in the carboxyl-terminal region in residues not expected to interact directly with the Type I receptor. Replacement of Ile143 with Thr in helix E significantly lowered receptor binding affinity to about 5% of control values, reduced antiviral activity to about 13% of control values, and abolished antiproliferative activity completely. Deletion of the terminal 11 residues from the carboxyl termini of these 172 amino acid IFN also reduced antiviral activities (approximately 5% of control) and antiproliferative proteins (1-2% of control), but had only slight negative influence on receptor binding. Deletion of Lys160, but not its replacement with Ala, had similar consequences to deleting the entire 11-amino acid carboxyl terminus. These studies show that mutations can be introduced into IFN-tau that influence antiviral and antiproliferative activities differentially and that the carboxyl tail of the molecule is important for signal transduction but not for primary receptor binding.
Li
J
J
Department of Biochemistry, University of Missouri, Columbia 65211.
Roberts
R M
RM
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004717:Endometrium / Q000378:metabolism; D005260:Female; D007370:Interferon Type I / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D011257:Pregnancy Proteins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017471:Receptors, Interferon / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis; D012756:Sheep; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D007370:Interferon Type I; D011257:Pregnancy Proteins; D017471:Receptors, Interferon; D011994:Recombinant Proteins; C020947:interferon tau