PROSITE documentation PDOC50139
Z-binding domain profile


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.

Last update:

April 2020 / Profile and text revised.


Technical section

PROSITE method (with tools and information) covered by this documentation:

Z_BINDING, PS50139; Z-binding domain profile  (MATRIX)


1AuthorsMaelfait J. Liverpool L. Bridgeman A. Ragan K.B. Upton J.W. Rehwinkel J.
TitleSensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis.
SourceEMBO. J. 36:2529-2543(2017).
PubMed ID28716805

2AuthorsLee A.-R. Hwang J. Hur J.H. Ryu K.-S. Kim K.K. Choi B.-S. Kim N.-K.
TitleLee J.-H. NMR Dynamics Study Reveals the Zalpha Domain of Human ADAR1 Associates with and Dissociates from Z-RNA More Slowly than Z-DNA.
SourceACS. Chem. Biol. 14:245-255(2019).
PubMed ID30592616

3AuthorsSchwartz T. Behlke J. Lowenhaupt K. Heinemann U. Rich A.
TitleStructure of the DLM-1-Z-DNA complex reveals a conserved family of Z-DNA-binding proteins.
SourceNat. Struct. Biol. 8:761-765(2001).
PubMed ID11524677

4AuthorsSubramani V.K. Kim D. Yun K. Kim K.K.
TitleStructural and functional studies of a large winged Z-DNA-binding domain of Danio rerio protein kinase PKZ.
SourceFEBS. Lett. 590:2275-2285(2016).
PubMed ID27265117

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