Z-DNA-binding protein 1 (ZBP1), also known as DAI (DNA-dependent activator of IFN regulatory factors), is a cytosolic DNA sensor that activates the innate immune system [].
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 characterised 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. This entry represents the Z-binding domain (ZBD), also referred to as Zalpha or Zbeta, which 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 [, , , , , ].The Z-binding domain displays an α/β architecture with three α-helices packed against three antiparallel β-strands (). 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 1is joined to helix 2 by a β-strand, beta1. C-terminal to helix 3 is the 'wing', formed by two antiparallel β-strands (β2 and β3), which hydrogen bond to each other and to beta1, forming a three-stranded β-sheet [, ].
