| Structural highlights
Function
ABC3G_HUMAN DNA deaminase (cytidine deaminase) that mediates a form of innate resistance to retroviral infections (at least to HIV-1 infection) by triggering G-to-A hypermutation in the newly synthesized viral DNA. The replacements C-to-U in the minus strand DNA of HIV-1 during reverse transcription, leads to G-to-A transitions in the plus strand. The inhibition of viral replication is either due to the degradation of the minus strand before its integration or to the lethality of the hypermutations. Modification of both DNA strands is not excluded. This antiviral activity is neutralized by the virion infectivity factor (VIF), that prevents the incorporation of APOBEC3G into progeny HIV-1 virions by both inhibiting its translation and/or by inducing its ubiquitination and subsequent degradation by the 26S proteasome. May also prevent the transposition of a subset of retroelements. Binds a variety of RNAs, but does not display detectable APOB, NF1 and NAT1 mRNA editing.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]
Publication Abstract from PubMed
The human APOBEC3G protein is a cytidine deaminase that generates cytidine to deoxy-uridine mutations in single-stranded DNA (ssDNA), and capable of restricting replication of HIV-1 by generating mutations in viral genome. The mechanism by which APOBEC3G specifically deaminates 5'-CC motifs has remained elusive since structural studies have been hampered due to apparently weak ssDNA binding of the catalytic domain of APOBEC3G. We overcame the problem by generating a highly active variant with higher ssDNA affinity. Here, we present the crystal structure of this variant complexed with a ssDNA substrate at 1.86 A resolution. This structure reveals atomic-level interactions by which APOBEC3G recognizes a functionally-relevant 5'-TCCCA sequence. This complex also reveals a key role of W211 in substrate recognition, implicating a similar recognition in activation-induced cytidine deaminase (AID) with a conserved tryptophan.
Crystal structure of the catalytic domain of HIV-1 restriction factor APOBEC3G in complex with ssDNA.,Maiti A, Myint W, Kanai T, Delviks-Frankenberry K, Sierra Rodriguez C, Pathak VK, Schiffer CA, Matsuo H Nat Commun. 2018 Jun 25;9(1):2460. doi: 10.1038/s41467-018-04872-8. PMID:29941968[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kao S, Khan MA, Miyagi E, Plishka R, Buckler-White A, Strebel K. The human immunodeficiency virus type 1 Vif protein reduces intracellular expression and inhibits packaging of APOBEC3G (CEM15), a cellular inhibitor of virus infectivity. J Virol. 2003 Nov;77(21):11398-407. PMID:14557625
- ↑ Sheehy AM, Gaddis NC, Choi JD, Malim MH. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature. 2002 Aug 8;418(6898):646-50. Epub 2002 Jul 14. PMID:12167863 doi:10.1038/nature00939
- ↑ Mangeat B, Turelli P, Caron G, Friedli M, Perrin L, Trono D. Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature. 2003 Jul 3;424(6944):99-103. Epub 2003 May 28. PMID:12808466 doi:10.1038/nature01709
- ↑ Harris RS, Bishop KN, Sheehy AM, Craig HM, Petersen-Mahrt SK, Watt IN, Neuberger MS, Malim MH. DNA deamination mediates innate immunity to retroviral infection. Cell. 2003 Jun 13;113(6):803-9. PMID:12809610
- ↑ Zhang H, Yang B, Pomerantz RJ, Zhang C, Arunachalam SC, Gao L. The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA. Nature. 2003 Jul 3;424(6944):94-8. Epub 2003 May 28. PMID:12808465 doi:10.1038/nature01707
- ↑ Mariani R, Chen D, Schrofelbauer B, Navarro F, Konig R, Bollman B, Munk C, Nymark-McMahon H, Landau NR. Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif. Cell. 2003 Jul 11;114(1):21-31. PMID:12859895
- ↑ Shindo K, Takaori-Kondo A, Kobayashi M, Abudu A, Fukunaga K, Uchiyama T. The enzymatic activity of CEM15/Apobec-3G is essential for the regulation of the infectivity of HIV-1 virion but not a sole determinant of its antiviral activity. J Biol Chem. 2003 Nov 7;278(45):44412-6. Epub 2003 Sep 11. PMID:12970355 doi:https://dx.doi.org/10.1074/jbc.C300376200
- ↑ Sheehy AM, Gaddis NC, Malim MH. The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif. Nat Med. 2003 Nov;9(11):1404-7. Epub 2003 Oct 5. PMID:14528300 doi:10.1038/nm945
- ↑ Turelli P, Mangeat B, Jost S, Vianin S, Trono D. Inhibition of hepatitis B virus replication by APOBEC3G. Science. 2004 Mar 19;303(5665):1829. PMID:15031497 doi:10.1126/science.1092066
- ↑ Chen H, Lilley CE, Yu Q, Lee DV, Chou J, Narvaiza I, Landau NR, Weitzman MD. APOBEC3A is a potent inhibitor of adeno-associated virus and retrotransposons. Curr Biol. 2006 Mar 7;16(5):480-5. PMID:16527742 doi:10.1016/j.cub.2006.01.031
- ↑ Bulliard Y, Narvaiza I, Bertero A, Peddi S, Rohrig UF, Ortiz M, Zoete V, Castro-Diaz N, Turelli P, Telenti A, Michielin O, Weitzman MD, Trono D. Structure-function analyses point to a polynucleotide-accommodating groove essential for APOBEC3A restriction activities. J Virol. 2011 Feb;85(4):1765-76. doi: 10.1128/JVI.01651-10. Epub 2010 Dec 1. PMID:21123384 doi:10.1128/JVI.01651-10
- ↑ Chen KM, Harjes E, Gross PJ, Fahmy A, Lu Y, Shindo K, Harris RS, Matsuo H. Structure of the DNA deaminase domain of the HIV-1 restriction factor APOBEC3G. Nature. 2008 Mar 6;452(7183):116-9. Epub 2008 Feb 20. PMID:18288108 doi:10.1038/nature06638
- ↑ Maiti A, Myint W, Kanai T, Delviks-Frankenberry K, Sierra Rodriguez C, Pathak VK, Schiffer CA, Matsuo H. Crystal structure of the catalytic domain of HIV-1 restriction factor APOBEC3G in complex with ssDNA. Nat Commun. 2018 Jun 25;9(1):2460. doi: 10.1038/s41467-018-04872-8. PMID:29941968 doi:https://dx.doi.org/10.1038/s41467-018-04872-8
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