Nucleic acids form double-stranded helices. Double-stranded (ds) DNA typically adopts the so-called B-conformation, while dsRNA is usually in the A-conformation. Both DNA and RNA can also adopt a Z-form double helix that is characterized by a left-handed helical arrangement, a zigzag pattern of the phosphodiester backbone and the absence of major grooves. Z-DNA is believed to play a role in transcription by relieving torsional strain induced within the DNA template by the movement of RNA polymerases, and Z-DNA may also promote genetic instability. Physiological functions of Z-RNA remain unknown. The Z-binding domain (ZBD), also referred to as Zα or Zβ is a 78-amino-acid protein fold that specifically binds to Z-DNA as well as to Z-RNA but not to B-DNA. ZBDs have been identified in four proteins: ADAR1, ZBP1, E3L and PKZ. ADAR1 and ZBP1 are mammalian proteins implicated in antiviral innate immune responses. E3L is a poxvirus protein known to antagonise this host response. Lastly, PKZ is a fish protein related to mammalian PKR, also involved in antiviral immunity. This suggests an important role of ZBDs in innate antiviral immune responses and may imply that Z-DNA and/or Z-RNA trigger such a host defense response [1,2,3,4].

The Z-binding domain displays an α/β architecture with three α-helices packed against three antiparallel β-strands (see <PDB:1J75>). It belongs to the winged helix-turn-helix (wHTH) domain superfamily. The three helices form the core of the domain, with helices 2 and 3 forming the helix-turn-helix unit. Helix 1 is joined to helix 2 by a β-strand, β1. C-terminal to helix 3 is the 'wing', formed by two antiparallel β-strands (β2 and β3), which hydrogen bond to each another and to β1, forming a three-stranded β-sheet [3,4].

Protein currently known to include a Z-binding domain are listed below:

• Mammalian RNA editing enzyme ADAR1 (or double stranded-specific adenosine deaminase, DRADA), deaminates adenosine in pre-mRNA to yield inosine, which codes as a guanine residue in mRNA.
• Mammalian Z-DNA binding protein 1 (ZBP1, also known as DAI or DLM-1), activates NF-kappaB and triggers necroptosis, an inflammatory form of programmed cell death. It has two N-terminal ZBDs (Zα1 and Zα2) and two RIP homotypic interaction motifs (RHIMs).
• Fish ZBP-containing protein kinase (PKZ), a RNA-dependent Protein Kinase (PKR)-like eukaryotic initiation factor 2 α (eIF2α) kinase, that plays a role in host defense mechanisms by recognizing foreign nucleic acids with its N-terminal Z-binding domain.
• Poxviral VEO3 protein.

The profile we developed covers the entire Z-binding domain.