1xmk

Structural highlights

Disease

DSRAD_HUMAN Defects in ADAR are a cause of dyschromatosis symmetrical hereditaria (DSH) [MIM:127400; also known as reticulate acropigmentation of Dohi. DSH is a pigmentary genodermatosis of autosomal dominant inheritance characterized by a mixture of hyperpigmented and hypopigmented macules distributed on the dorsal parts of the hands and feet.^{[1] [2] [3]}

Function

DSRAD_HUMAN Catalyzes the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) referred to as A-to-I RNA editing. This may affect gene expression and function in a number of ways that include mRNA translation by changing codons and hence the amino acid sequence of proteins; pre-mRNA splicing by altering splice site recognition sequences; RNA stability by changing sequences involved in nuclease recognition; genetic stability in the case of RNA virus genomes by changing sequences during viral RNA replication; and RNA structure-dependent activities such as microRNA production or targeting or protein-RNA interactions. Can edit both viral and cellular RNAs and can edit RNAs at multiple sites (hyper-editing) or at specific sites (site-specific editing). Its cellular RNA substrates include: bladder cancer-associated protein (BLCAP), neurotransmitter receptors for glutamate (GRIA2) and serotonin (HTR2C) and GABA receptor (GABRA3). Site-specific RNA editing of transcripts encoding these proteins results in amino acid substitutions which consequently alters their functional activities. Exhibits low-level editing at the GRIA2 Q/R site, but edits efficiently at the R/G site and HOTSPOT1. Its viral RNA substrates include: hepatitis C virus (HCV), vesicular stomatitis virus (VSV), measles virus (MV), hepatitis delta virus (HDV), and human immunodeficiency virus type 1 (HIV-1). Exhibits either a proviral (HDV, MV, VSV and HIV-1) or an antiviral effect (HCV) and this can be editing-dependent (HDV and HCV), editing-independent (VSV and MV) or both (HIV-1). Impairs HCV replication via RNA editing at multiple sites. Enhances the replication of MV, VSV and HIV-1 through an editing-independent mechanism via suppression of EIF2AK2/PKR activation and function. Stimulates both the release and infectivity of HIV-1 viral particles by an editing-dependent mechanism where it associates with viral RNAs and edits adenosines in the 5'UTR and the Rev and Tat coding sequence. Can enhance viral replication of HDV via A-to-I editing at a site designated as amber/W, thereby changing an UAG amber stop codon to an UIG tryptophan (W) codon that permits synthesis of the large delta antigen (L-HDAg) which has a key role in the assembly of viral particles. However, high levels of ADAR1 inhibit HDV replication.^{[4] [5] [6] [7] [8] [9] [10] [11] [12] [13]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• Adenosine deaminase 3D structures

References

1. ↑ Miyamura Y, Suzuki T, Kono M, Inagaki K, Ito S, Suzuki N, Tomita Y. Mutations of the RNA-specific adenosine deaminase gene (DSRAD) are involved in dyschromatosis symmetrica hereditaria. Am J Hum Genet. 2003 Sep;73(3):693-9. Epub 2003 Aug 11. PMID:12916015 doi:http://dx.doi.org/10.1086/378209
2. ↑ Zhang XJ, He PP, Li M, He CD, Yan KL, Cui Y, Yang S, Zhang KY, Gao M, Chen JJ, Li CR, Jin L, Chen HD, Xu SJ, Huang W. Seven novel mutations of the ADAR gene in Chinese families and sporadic patients with dyschromatosis symmetrica hereditaria (DSH). Hum Mutat. 2004 Jun;23(6):629-30. PMID:15146470 doi:10.1002/humu.9246
3. ↑ Li CR, Li M, Ma HJ, Luo D, Yang LJ, Wang DG, Zhu XH, Yue XZ, Chen WQ, Zhu WY. A new arginine substitution mutation of DSRAD gene in a Chinese family with dyschromatosis symmetrica hereditaria. J Dermatol Sci. 2005 Feb;37(2):95-9. Epub 2004 Dec 21. PMID:15659327 doi:S0923-1811(04)00261-0
4. ↑ Yang W, Wang Q, Howell KL, Lee JT, Cho DS, Murray JM, Nishikura K. ADAR1 RNA deaminase limits short interfering RNA efficacy in mammalian cells. J Biol Chem. 2005 Feb 4;280(5):3946-53. Epub 2004 Nov 19. PMID:15556947 doi:M407876200
5. ↑ Taylor DR, Puig M, Darnell ME, Mihalik K, Feinstone SM. New antiviral pathway that mediates hepatitis C virus replicon interferon sensitivity through ADAR1. J Virol. 2005 May;79(10):6291-8. PMID:15858013 doi:10.1128/JVI.79.10.6291-6298.2005
6. ↑ Hartwig D, Schutte C, Warnecke J, Dorn I, Hennig H, Kirchner H, Schlenke P. The large form of ADAR 1 is responsible for enhanced hepatitis delta virus RNA editing in interferon-alpha-stimulated host cells. J Viral Hepat. 2006 Mar;13(3):150-7. PMID:16475990 doi:10.1111/j.1365-2893.2005.00663.x
7. ↑ Nie Y, Hammond GL, Yang JH. Double-stranded RNA deaminase ADAR1 increases host susceptibility to virus infection. J Virol. 2007 Jan;81(2):917-23. Epub 2006 Nov 1. PMID:17079286 doi:10.1128/JVI.01527-06
8. ↑ Toth AM, Li Z, Cattaneo R, Samuel CE. RNA-specific adenosine deaminase ADAR1 suppresses measles virus-induced apoptosis and activation of protein kinase PKR. J Biol Chem. 2009 Oct 23;284(43):29350-6. doi: 10.1074/jbc.M109.045146. Epub 2009, Aug 25. PMID:19710021 doi:10.1074/jbc.M109.045146
9. ↑ Clerzius G, Gelinas JF, Daher A, Bonnet M, Meurs EF, Gatignol A. ADAR1 interacts with PKR during human immunodeficiency virus infection of lymphocytes and contributes to viral replication. J Virol. 2009 Oct;83(19):10119-28. doi: 10.1128/JVI.02457-08. Epub 2009 Jul 15. PMID:19605474 doi:10.1128/JVI.02457-08
10. ↑ Doria M, Neri F, Gallo A, Farace MG, Michienzi A. Editing of HIV-1 RNA by the double-stranded RNA deaminase ADAR1 stimulates viral infection. Nucleic Acids Res. 2009 Sep;37(17):5848-58. doi: 10.1093/nar/gkp604. Epub 2009, Aug 3. PMID:19651874 doi:10.1093/nar/gkp604
11. ↑ Galeano F, Leroy A, Rossetti C, Gromova I, Gautier P, Keegan LP, Massimi L, Di Rocco C, O'Connell MA, Gallo A. Human BLCAP transcript: new editing events in normal and cancerous tissues. Int J Cancer. 2010 Jul 1;127(1):127-37. doi: 10.1002/ijc.25022. PMID:19908260 doi:10.1002/ijc.25022
12. ↑ Doria M, Tomaselli S, Neri F, Ciafre SA, Farace MG, Michienzi A, Gallo A. ADAR2 editing enzyme is a novel human immunodeficiency virus-1 proviral factor. J Gen Virol. 2011 May;92(Pt 5):1228-32. doi: 10.1099/vir.0.028043-0. Epub 2011, Feb 2. PMID:21289159 doi:10.1099/vir.0.028043-0
13. ↑ Li Z, Okonski KM, Samuel CE. Adenosine deaminase acting on RNA 1 (ADAR1) suppresses the induction of interferon by measles virus. J Virol. 2012 Apr;86(7):3787-94. doi: 10.1128/JVI.06307-11. Epub 2012 Jan 25. PMID:22278222 doi:10.1128/JVI.06307-11