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The Role of 2', 5'-Oligoadenylate Synthetase Gene in Interferon System

2,5-寡腺苷酸合成酶基因在干扰素系统中的作用

基本信息

批准号：
10680608
负责人：
SOKAWA Yoshihiro
金额：
$ 2.11万
依托单位：
KYOTO INSTITUTE OF TECHNOLOGY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

2', 5'-Olioadenylate synthetase (OAS), an interferon (IFN)-induced enzyme, is activated by double-stranded RNA and synthesizes 2', 5'-oligoadenylate (2-5A) using ATP as a substrate. The following results were obtained from the research aided by this grant.(1) A P-loop motif followed by an Asp-containing sequence (referred to as D-box) and a region with a high content of Lys and Arg (KR-rich region) are conserved in various OAS subtypes. The experiments of the site-directed mutations into these motifs demonstrated that these motifs are important for the enzymatic activities of OAS : MgィイD12+ィエD1 binds to the D-box and ATP may interact to both P-loop and KR-rich region.(2) The gene for ChOAS is composed of 6 exons and 5 introns, in which the 6th exon encodes an ubiquitin-like (UbL) domain and the 1st to 5th exons encode the catalytic domain. The ChOAS gene has at least two alleles, OASィイD1*ィエD1A and OASィイD1*ィエD1B, and OASィイD1*ィエD1B allele was found only in Leghorn among various chicken lines. OAS-B has a deletion of 32-amino acids in the UbL domain.(3) When compared the enzymatic nature between OAS-A and B, OAS-B was more labile to heat-treatment and denatured at low temperature. Furthermore, OAS-B was more sensitive to protease-treatment and digested easily. These results indicate that the UbL domain stabilizes the conformation of the catalytic domain of this enzyme.(4) In addition to the above results, the target sites of IFN action in tissues were determined by the induction of OAS.

2', 5'-寡腺苷酸合成酶（OAS）是干扰素（IFN）诱导的酶，由双链RNA激活，以ATP为底物合成2',5'-寡腺苷酸（2- 5a）。下列结果是由这项拨款资助的研究所得。(1)在各种OAS亚型中，P-loop基序后面有一个含有asp的序列（称为D-box）和一个富含Lys和Arg的区域（富含kr的区域）是保守的。这些基序的位点定向突变实验表明，这些基序对OAS的酶活性很重要：Mg γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ。(2) ChOAS基因由6个外显子和5个内含子组成，其中第6外显子编码泛素样（UbL）结构域，第1 ~ 5外显子编码催化结构域。ChOAS基因至少有两个等位基因，即OAS γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ。OAS-B在UbL结构域缺失32个氨基酸。(3)对比OAS-A和B的酶促性质，OAS-B更容易热处理，在低温下更易变性。此外，OAS-B对蛋白酶处理更敏感，易于消化。这些结果表明，UbL结构域稳定了该酶的催化结构域的构象。(4)除上述结果外，还通过诱导OAS确定了IFN在组织中的作用靶位。