Characterization of N-terminal interferon tau mutants: P26L affords enhanced activity and lack of toxicity.
Interferon (IFN)-tau is a type I IFN that is responsible for the maternal recognition of pregnancy in ruminants. This protein also has classic IFN-like properties, including antiviral, antiproliferative, and immunomodulatory functions. Using IFN-tau as a model, we examined the structural basis for the activity of type I IFNs, focusing on amino acids within helix A and the first section of the AB loop, which have been proposed as a site for receptor interaction. Six amino-acid substitutions were made that replaced a residue in ovine IFN-tau1mod with the corresponding residue in human IFN-alphaA. Receptor binding was enhanced by a P26L mutation and was reduced by a conservative lysine-to-histidine substitution at residue 34. Alterations in the antiviral and antiproliferative activities of the IFN-tau mutants were not always correlated, but both functions were maintained or enhanced relative to the wild-type IFN-tau by the proline-to-leucine mutation at residue 26. In contrast, this mutation did not affect the low in vitro cytotoxicity that is characteristic of ovine IFN-tau1mod. Thus, the IFN-tau P26L mutant may have potential as an improved IFN-based therapeutic.
Shorts
Lynnette H
LH
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA.
Dancz
Christina E
CE
Shupp
Jeffrey W
JW
Pontzer
Carol H
CH
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival; D006801:Humans; D007370:Interferon Type I / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D010843:Pichia / Q000378:metabolism; D011257:Pregnancy Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D011869:Radioligand Assay; D017471:Receptors, Interferon / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D012756:Sheep; D015534:Trans-Activators / Q000378:metabolism
D000998:Antiviral Agents; D007370:Interferon Type I; D011257:Pregnancy Proteins; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D015534:Trans-Activators; C020947:interferon tau