ADAR

1QBJ, 1QGP, 1XMK, 2ACJ, 2GXB, 2L54, 2MDR, 3F21, 3F22, 3F23, 3IRQ, 3IRR10356417ENSG00000160710ENSMUSG00000027951P55265Q99MU3NM_001365045NM_001365046NM_001365047NM_001365048NM_001365049NM_001038587NM_001146296NM_019655NM_001357958NP_001020278NP_001102NP_001180424NP_056655NP_056656NP_001033676NP_001139768NP_062629NP_001344887Double-stranded RNA-specific adenosine deaminase is an enzyme that in humans is encoded by the ADAR gene (which stands for adenosine deaminase acting on RNA).scheme of adenosine conversion to inosine via ADAR1qbj: CRYSTAL STRUCTURE OF THE ZALPHA Z-DNA COMPLEX1qgp: NMR STRUCTURE OF THE Z-ALPHA DOMAIN OF ADAR1, 15 STRUCTURES1xmk: The Crystal structure of the Zb domain from the RNA editing enzyme ADAR12acj: Crystal structure of the B/Z junction containing DNA bound to Z-DNA binding proteins2gxb: Crystal Structure of The Za Domain bound to Z-RNA Double-stranded RNA-specific adenosine deaminase is an enzyme that in humans is encoded by the ADAR gene (which stands for adenosine deaminase acting on RNA). Adenosine deaminases acting on RNA (ADAR) are enzymes responsible for binding to double stranded RNA (dsRNA) and converting adenosine (A) to inosine (I) by deamination. ADAR protein is a RNA-binding protein, which functions in RNA-editing through post-transcriptional modification of mRNA transcripts by changing the nucleotide content of the RNA. The conversion from A to I in the RNA disrupt the normal A:U pairing which makes the RNA unstable. Inosine is structurally similar to that of guanine (G) which leads to I to cytosine (C) binding. Inosine typically mimicks guanosine during translation. Codon changes can arise from editing which may lead to changes in the coding sequences for proteins and their functions. Most editing sites are found in noncoding regions of RNA such as untranslated regions (UTRs), Alu elements, and long interspersed nuclear element (LINEs). Mutations in this gene have been associated with dyschromatosis symmetrica hereditaria, as well as Aicardi–Goutières syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. ADAR also impacts the transcriptome in editing-independent ways, likely by interfering with other RNA-binding proteins. Adenosine deaminase acting on RNA (ADAR) and its gene were first discovered accidentally in 1987 as a result of research by Brenda Bass and Harold Weintraub. These researchers were using antisense RNA inhibition to determine which genes play a key role in the development of Xenopus leavis embryos. Previous research on Xenopus oocytes had been successful. However, when Bass and Weintraub applied identical protocols to Xenopus embryos, they were unable to determine the embryo’s developmental genes. In an attempt to understand why the method was unsuccessful, they began comparing duplex RNA in both oocytes and embryos. This led them to discover that a developmentally regulated activity denatures RNA:RNA hybrids in embryos. In 1988, Richard Wagner et al. further studied the activity occurring on Xenopus embryos. They determined that a protein was responsible for the unwinding of RNA due to the absence of activity after proteinase treatment. It was also shown that this protein is specific for double stranded RNA, or dsRNA, and does not require ATP. Additionally, it became evident that the protein’s activity on dsRNA modifies it beyond a point of rehybridization, but does not fully denature it. Finally, the researchers determined that this unwinding is due to the deamination of adenosine residues to inosine. This modification results in mismatched base-pairing between inosine and uridine, leading to the destabilization and unwinding of dsRNA. Adenosine Deaminase Acting on RNA is one of the most common forms of RNA editing, and has both selective and non-selective activity. ADAR is able to both modify and regulate the output of gene product, as inosine is interpreted by the cell to be guanosine. ADAR has also been determined to change the functionality of small RNA molecules. It is believed that ADAR evolved from ADAT (Adenosine Deaminase Acting on tRNA), a critical protein present in all eukaryotes, early in the metazoan period through the addition of a dsRNA binding domain. This likely occurred in the lineage which leads to the crown Metazoa when a duplicate ADAT gene was coupled to a gene encoding at least one double stranded RNA binding. The ADAR family of genes has been largely conserved over the history of its existence. This, along with its presence in the majority of modern phyla, indicates that RNA editing is an essential regulatory gene for metazoan organisms. ADAR has not been discovered in a variety of non-metazoan eukaryotes, such as plants, fungi and choanoflagellates. In mammals, there are three types of ADARs, 1, 2 and 3. ADAR1 and ADAR2 are found in many tissues in the body while ADAR3 is only found in the brain. ADAR1 and ADAR2 are known to be catalytically active while ADAR3 is thought to be inactive. ADAR1 has two known isoforms known as ADAR1p150 and ADAR1p110. ADAR1p110 is usually only found in the nucleus while ADAR1p150 shuffles between the nucleus to the cytoplasm and is mostly present in the cytoplasm. Although ADAR1 and ADAR2 share many common functional domains as well as commonality in terms of expression pattern, structure of protein and requirements of substrates having double stranded RNA structures, they differ in their editing activity. ADARs catalyze the reaction from A to I by hydrolytic deamination. It does this by the use of an activated water molecule for a nucelophilic attack. It is done by the addition of water to carbon 6 and removal of ammonia with a hydrated intermediate.