Zalpha

Z-DNA-binding domain in adenosine deaminases.

• SMART accession number: SM00550
• Description: Helix-turn-helix-containing domain. Also known as Zab.
• Interpro abstract (IPR042371):

  This entry represents the z-alpha domain found in double-stranded RNA-specific adenosine deaminase (ADAR), an RNA-editing enzyme. The z-alpha domain is a Z-DNA binding domain [ (PUBMED:10535945) ]. This domain can also be found in Z-DNA-binding protein 1, a cytosolic DNA sensor that activates the innate immune system [ (PUBMED:17618271) ].

There are 934 Zalpha domains in 478 proteins in SMART's nrdb database.

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Schade M et al.
• The solution structure of the Zalpha domain of the human RNA editing enzyme ADAR1 reveals a prepositioned binding surface for Z-DNA.
• Proc Natl Acad Sci U S A. 1999; 96: 12465-70

Double-stranded RNA deaminase I (ADAR1) contains the Z-DNA binding domain Zalpha. Here we report the solution structure of free Zalpha and map the interaction surface with Z-DNA, confirming roles previously assigned to residues by mutagenesis. Comparison with the crystal structure of the (Zalpha)(2)/Z-DNA complex shows that most Z-DNA contacting residues in free Zalpha are prepositioned to bind Z-DNA, thus minimizing the entropic cost of binding. Comparison with homologous (alpha+beta)helix-turn-helix/B-DNA complexes suggests that binding of Zalpha to B-DNA is disfavored by steric hindrance, but does not eliminate the possibility that related domains may bind to both B- and Z-DNA.

• Schwartz T, Rould MA, Lowenhaupt K, Herbert A, Rich A
• Crystal structure of the Zalpha domain of the human editing enzyme ADAR1 bound to left-handed Z-DNA.
• Science. 1999; 284: 1841-5

The editing enzyme double-stranded RNA adenosine deaminase includes a DNA binding domain, Zalpha, which is specific for left-handed Z-DNA. The 2.1 angstrom crystal structure of Zalpha complexed to DNA reveals that the substrate is in the left-handed Z conformation. The contacts between Zalpha and Z-DNA are made primarily with the "zigzag" sugar-phosphate backbone, which provides a basis for the specificity for the Z conformation. A single base contact is observed to guanine in the syn conformation, characteristic of Z-DNA. Intriguingly, the helix-turn-helix motif, frequently used to recognize B-DNA, is used by Zalpha to contact Z-DNA.

• Herbert A et al.
• The Zalpha domain from human ADAR1 binds to the Z-DNA conformer of many different sequences.
• Nucleic Acids Res. 1998; 26: 3486-93

Z-DNA, the left-handed conformer of DNA, is stabilized by the negative supercoiling generated during the movement of an RNA polymerase through a gene. Recently, we have shown that the editing enzyme ADAR1 (double-stranded RNA adenosine deaminase, type 1) has two Z-DNA binding motifs, Zalpha and Zbeta, the function of which is currently unknown. Here we show that a peptide containing the Zalpha motif binds with high affinity to Z-DNA as a dimer, that the binding site is no larger than 6 bp and that the Zalpha domain can flip a range of sequences, including d(TA)3, into the Z-DNAconformation. Evidence is also presented to show that Zalpha and Zbeta interact to form a functional DNA binding site. Studies with atomic force microscopy reveal that binding of Zalpha to supercoiled plasmids is associated with relaxation of the plasmid. Pronounced kinking of DNA is observed, and appears to be induced by binding of Zalpha. The results reported here support a model where the Z-DNA binding motifs target ADAR1 to regions of negative supercoiling in actively transcribing genes. In this situation, binding by Zalpha would be dependent upon the local level of negative superhelicity rather than the presence of any particular sequence.

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
100.00	map00791	Atrazine degradation

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with Zalpha domain which could be assigned to a KEGG orthologous group, and not all proteins containing Zalpha domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of Zalpha domains in PDB

PDB code	Title
1j75	Crystal Structure of the DNA-Binding Domain Zalpha of DLM-1 Bound to Z-DNA
1oyi	Solution structure of the Z-DNA binding domain of the vaccinia virus gene E3L
1qbj	CRYSTAL STRUCTURE OF THE ZALPHA Z-DNA COMPLEX
1qgp	NMR STRUCTURE OF THE Z-ALPHA DOMAIN OF ADAR1, 15 STRUCTURES
1sfu	Crystal structure of the viral Zalpha domain bound to left-handed Z-DNA
1xmk	The Crystal structure of the Zb domain from the RNA editing enzyme ADAR1
2acj	Crystal structure of the B/Z junction containing DNA bound to Z-DNA binding proteins
2gxb	Crystal Structure of The Za Domain bound to Z-RNA
2heo	General Structure-Based Approach to the Design of Protein Ligands: Application to the Design of Kv1.2 Potassium Channel Blockers.
2l4m	Solution structure of the Zbeta domain of human DAI and its binding modes to B- and Z-DNA
2l54	Solution structure of the Zalpha domain mutant of ADAR1 (N43A,Y47A)
2lnb	Solution NMR structure of N-terminal domain (6-74) of human ZBP1 protein, Northeast Structural Genomics Consortium Target HR8174A.
2rvc	2RVC
3eyi	The crystal structure of the second Z-DNA binding domain of human DAI (ZBP1) in complex with Z-DNA
3f21	Crystal structure of Zalpha in complex with d(CACGTG)
3f22	Crystal structure of Zalpha in complex with d(CGTACG)
3f23	Crystal structure of Zalpha in complex with d(CGGCCG)
3irq	Crystal structure of a Z-Z junction
3irr	Crystal Structure of a Z-Z junction (with HEPES intercalating)
4hob	The crystal structure of the Zalpha domain from Cyprinid Herpes virus 3
4ka4	Crystal structure of a proteolytically defined Zbeta domain of human DAI (ZBP1, DLM-1)
4kmf	Crystal structure of Zalpha domain from Carassius auratus PKZ in complex with Z-DNA
4lb5	Crystal structure of PKZ Zalpha in complex with ds(CG)6 (hexagonal form)
4lb6	Crystal structure of PKZ Zalpha in complex with ds(CG)6 (tetragonal form)
4wcg	4WCG
5j6x	5J6X

Links (links to other resources describing this domain)

• INTERPRO: IPR042371