Shorts Lynnette H, Dancz Christina E, Shupp Jeffrey W, Pontzer Carol H
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA.
Exp Biol Med (Maywood). 2004 Feb;229(2):194-202. doi: 10.1177/153537020422900208.
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.
干扰素（IFN）-τ是一种I型干扰素，负责反刍动物妊娠的母体识别。这种蛋白质还具有典型的干扰素样特性，包括抗病毒、抗增殖和免疫调节功能。以IFN-τ为模型，我们研究了I型干扰素活性的结构基础，重点关注A螺旋和AB环第一部分内的氨基酸，这些氨基酸被认为是受体相互作用的位点。进行了六个氨基酸替换，将绵羊IFN-τ1mod中的一个残基替换为人IFN-αA中的相应残基。P26L突变增强了受体结合，而34位残基处保守的赖氨酸到组氨酸替换则降低了受体结合。IFN-τ突变体的抗病毒和抗增殖活性的改变并不总是相关的，但相对于野生型IFN-τ，26位残基处的脯氨酸到亮氨酸突变使这两种功能得以维持或增强。相比之下，这种突变并不影响绵羊IFN-τ1mod特有的低体外细胞毒性。因此，IFN-τ P26L突变体可能具有作为改进的基于干扰素的治疗药物的潜力。
