2',5'-Oligoadenylate synthetase (2',5'-OAS) was discovered and characterized as an interferon (IFN)-induced enzyme that in the presence of double-stranded (ds) RNA converts ATP into 2',5'-linked oligomers of adenosine with the general formula pppA(2'p'A)n, n > or = 1. The product is pppG2'p5'G when GTP is used as a substrate. Now, 20 years later, this activity is attributed to several well-characterized, homologous, and IFN-induced proteins in human cells. Three distinct forms of 2',5'-OAS exist, small, medium, and large, which contain 1, 2, and 3 OAS units, respectively, and are encoded by distinct genes clustered on the 2',5'-OAS locus on human chromosome 12. Recently, other IFN-induced proteins homologous to the OAS unit but devoid of the typical 2',5'-OAS catalytic activity have been described. These OAS-related proteins are encoded by a gene located at the proximity of the 2',5'-OAS locus. These findings illustrate the apparent structural and functional complexity of the human 2',5'-OAS family.

The Human 2',5'-Oligoadenylate Synthetase Family: Interferon-Induced Proteins with Unique Enzymatic Properties

The 69-kDa 2-5A synthetase is composed of two homologous and adjacent functional domains.

Enzymatic Activity of 2′–5′-Oligoadenylate Synthetase Is Impaired by Specific Mutations that Affect Oligomerization of the Protein

The members of the oligoadenylate synthetase (OAS) family of proteins are antiviral restriction factors that target a wide range of RNA and DNA viruses. They function as intracellular double-stranded RNA (dsRNA) sensors that, upon binding to dsRNA, undergo a conformational change and are activated to synthesize 2′-5′-linked oligoadenylates (2-5As). 2-5As of sufficient length act as second messengers to activate RNase L and thereby restrict viral replication. We expressed human OAS3 using the baculovirus system and purified it to homogeneity. We show that recombinant OAS3 is activated at a substantially lower concentration of dsRNA than OAS1, making it a potent in vivo sensor of dsRNA. Moreover, we find that OAS3 synthesizes considerably longer 2-5As than previously reported, and that OAS3 can activate RNase L intracellularly. The combined high affinity for dsRNA and the capability to produce 2-5As of sufficient length to activate RNase L suggests that OAS3 is a potent activator of RNase L. In addition, we provide experimental evidence to support one active site of OAS3 located in the C-terminal OAS domain and generate a low-resolution structure of OAS3 using SAXS. IMPORTANCE We are the first to purify the OAS3 enzyme to homogeneity, which allowed us to characterize the mechanism utilized by OAS3 and identify the active site. We provide compelling evidence that OAS3 can produce 2′-5′-oligoadenylates of sufficient length to activate RNase L. This is contrary to what is described in the current literature but agrees with recent in vivo data showing that OAS3 harbors an antiviral activity requiring RNase L. Thus, our work redefines our understanding of the biological role of OAS3. Furthermore, we used a combination of mutagenesis and small-angle X-ray scattering to describe the active site and low-resolution structure of OAS3.

The 2′-5′-Oligoadenylate Synthetase 3 Enzyme Potently Synthesizes the 2′-5′-Oligoadenylates Required for RNase L Activation

Activation of Interferon-inducible 2′5′ Oligoadenylate Synthetase by Adenoviral VAI RNA

We have isolated and characterized two types of cDNA clones corresponding to interferon (IFN)-induced 1.6- and 1.8-kb mRNAs, as encoding two different forms of the 2′,5′-oligoadenylate (2′...

Production of two human 2',5'-oligoadenylate synthetase enzymes in Escherichia coli.

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Production of two human 2',5'-oligoadenylate synthetase enzymes in Escherichia coli.