{PDOC50139}
{PS50139; Z_BINDING}
{BEGIN}
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* Z-binding domain profile *
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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 Zalpha or Zbeta 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  alpha/beta architecture with three alpha-
helices packed  against  three  antiparallel beta-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 beta-strand, beta1.
C-terminal to  helix  3 is the 'wing', formed by two antiparallel beta-strands
(beta2 and beta3), which hydrogen bond to each another and to beta1, forming a
three-stranded beta-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 (Zalpha1 and Zalpha2) and
   two RIP homotypic interaction motifs (RHIMs).
 - Fish  ZBP-containing  protein  kinase (PKZ), a RNA-dependent Protein Kinase
   (PKR)-like eukaryotic  initiation  factor  2 alpha (eIF2alpha) 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.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.
-Last update: April 2020 / Profile and text revised.

[ 1] Maelfait J., Liverpool L., Bridgeman A., Ragan K.B., Upton J.W.,
     Rehwinkel J.
     "Sensing of viral and endogenous RNA by ZBP1/DAI induces
     necroptosis."
     EMBO. J. 36:2529-2543(2017).
     PubMed=28716805; DOI=10.15252/embj.201796476
[ 2] Lee A.-R., Hwang J., Hur J.H., Ryu K.-S., Kim K.K., Choi B.-S., Kim N.-K.,
     Lee J.-H.
     "NMR Dynamics Study Reveals the Zalpha Domain of Human ADAR1
     Associates with and Dissociates from Z-RNA More Slowly than Z-DNA."
     ACS. Chem. Biol. 14:245-255(2019).
     PubMed=30592616; DOI=10.1021/acschembio.8b00914
[ 3] Schwartz T., Behlke J., Lowenhaupt K., Heinemann U., Rich A.
     "Structure of the DLM-1-Z-DNA complex reveals a conserved family of
     Z-DNA-binding  proteins."
     Nat. Struct. Biol. 8:761-765(2001).
     PubMed=11524677; DOI=10.1038/nsb0901-761
[ 4] Subramani V.K., Kim D., Yun K., Kim K.K.
     "Structural and functional studies of a large winged Z-DNA-binding
     domain of Danio rerio protein kinase PKZ."
     FEBS. Lett. 590:2275-2285(2016).
     PubMed=27265117; DOI=10.1002/1873-3468.12238

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