Abstract
The RNA-dependent protein kinase PKR plays a central role in the antiviral defense of vertebrates by shutting down protein translation upon detection of viral dsRNA in the cytoplasm. In some teleost fish, PKZ, a homolog of PKR, performs the same function, but surprisingly, instead of dsRNA binding domains, it harbors two Z-DNA/Z-RNA-binding domains belonging to the Zalpha domain family. Zalpha domains have also been found in other proteins, which have key roles in the regulation of interferon responses such as ADAR1 and DNA-dependent activator of IFN-regulatory factors (DAI) and in viral proteins involved in immune response evasion such as the poxviral E3L and the Cyprinid Herpesvirus 3 ORF112. The underlying mechanism of nucleic acids binding and stabilization by Zalpha domains is still unclear. Here, we present two crystal structures of the zebrafish PKZ Zalpha domain (DrZalphaPKZ) in alternatively organized complexes with a (CG)6 DNA oligonucleotide at 2 and 1.8 Å resolution. These structures reveal novel aspects of the Zalpha interaction with DNA, and they give insights on the arrangement of multiple Zalpha domains on DNA helices longer than the minimal binding site.
Highlights
In mammals, two interferon inducible proteins, ADAR1 and dependent activator of IFN-regulatory factors (DAI), contain Zalpha domains, which is the first protein motif that has been found to recognize the high-energy conformation of double-stranded DNA known as Z-DNA
Two interferon inducible proteins, ADAR1 and DAI, contain Zalpha domains, which is the first protein motif that has been found to recognize the high-energy conformation of double-stranded DNA known as Z-DNA
In addition to revealing the characteristics of the DrZalphaPKZ protein domain, this is the first structure of a Zalpha domain where the CpG repeats in the bound DNA extend beyond the minimal (CG)3 binding site without interruption of the dinucleotide repeat
Summary
Two interferon inducible proteins, ADAR1 and DAI, contain Zalpha domains, which is the first protein motif that has been found to recognize the high-energy conformation of double-stranded DNA known as Z-DNA. Mutations within the Zalpha domain of the ADAR1 RNA editing enzyme, to those in the ADAR1 catalytic domain, are shown to cause the Aicardi Goutieres syndrome [2], an autoimmune condition. This indicates a role of ADAR1 and its Zalpha domain in nucleic acids clearance and suppression of type I interferon signaling. Viral double-stranded RNA is the signal that activates PKR, and this activation is mediated by its two N-terminal dsRNA binding domains (dsRBD). The available evidence suggests that both nucleic acids interacting domains of E3L are required for full inhibition of antiviral responses [6,7] and that they compete with cellular pathogen-associated molecular pattern sensors like PKR and DAI to control their responses and evade detection
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