Adenosine deaminase z-alpha domain

Available protein structures:
PDB	IPR000607 PF02295 (ECOD; PDBsum)
AlphaFold	IPR000607; PF02295;

Adenosine deaminase z-alpha domain
Adenosine deaminase z-alpha domain
	Crystal structure of the zb domain from the RNA editing enzyme ADAR1
Identifiers
Symbol	z-alpha
Pfam	PF02295
Pfam clan	CL0123
InterPro	IPR000607
SCOP2	1qgp / SCOPe / SUPFAM
PDB
Available protein structures:
PDB	IPR000607 PF02295 (ECOD; PDBsum)
AlphaFold	IPR000607; PF02295;

In molecular biology, the protein domain Adenosine deaminase z-alpha domain refers to an evolutionary conserved protein domain. This family consists of the N-terminus and thus the z-alpha domain of double-stranded RNA-specific adenosine deaminase (ADAR), an RNA-editing enzyme. The z-alpha domain is a Z-DNA binding domain, and binding of this region to B-DNA has been shown to be disfavoured by steric hindrance.^[1]

Function

Double-stranded RNA-specific adenosine deaminase (EC) converts multiple adenosines to inosines and creates I/U mismatched base pairs in double-helical RNA substrates without apparent sequence specificity. DRADA has been found to modify adenosines in AU-rich regions more frequently, probably due to the relative ease of melting A/U base pairs compared to G/C base pairs. The protein functions to modify viral RNA genomes, and may be responsible for hypermutation of certain negative-stranded viruses. DRADA edits the mRNAs for the glutamate receptor subunits by site-selective adenosine deamination. The DRADA repeat is also found in viral E3 proteins, which contain a double-stranded RNA-binding domain.

The Z-alpha domain is characteristic of the interferon-inducible p150 isoform of ADAR1. It targets the enzyme to endogenous Z-RNA structures, such as those formed by Alu elements; this editing is required to prevent the innate immune sensor MDA5 from triggering an interferon response.^[2]

Clinical significance

Mutations in the Z-alpha domain of ADAR1 are a cause of Aicardi-Goutières syndrome (AGS), an inflammatory encephalopathy associated with high levels of interferon-alpha. Specific mutations such as P193A and N173S result in Aicardi-Goutières syndrome type 6 (AGS6) because the failure to edit self-RNA triggers a type I interferon signature.^[3]^[2]

Examples

Genes encoding proteins containing this domain include ADAR and ZBP1.

References

↑ Schade M, Turner CJ, Kühne R, Schmieder P, Lowenhaupt K, Herbert A, Rich A, Oschkinat H (October 1999). "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. 96 (22): 12465–70. Bibcode:1999PNAS...9612465S. doi:10.1073/pnas.96.22.12465. PMC 22950. PMID 10535945.
1 2 de Reuver LC, et al. (2021). "ADAR1 interaction with Z-RNA promotes editing of endogenous double-stranded RNA and prevents MDA5-dependent immune activation". Immunity.
↑ Rice GI, et al. (2012). "Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature". Nature Genetics.

This article incorporates text from the public domain Pfam and InterPro: IPR000607

[pmid10535945-1] Schade M, Turner CJ, Kühne R, Schmieder P, Lowenhaupt K, Herbert A, Rich A, Oschkinat H (October 1999). "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. 96 (22): 12465–70. Bibcode:1999PNAS...9612465S. doi:10.1073/pnas.96.22.12465. PMC 22950. PMID 10535945.

[deReuver2021-2] 1 2 de Reuver LC, et al. (2021). "ADAR1 interaction with Z-RNA promotes editing of endogenous double-stranded RNA and prevents MDA5-dependent immune activation". Immunity.

[Rice2012-3] Rice GI, et al. (2012). "Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature". Nature Genetics.

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