| 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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The APOBEC family members are involved in diverse biological functions. APOBEC3G restricts the replication of human immunodeficiency virus (HIV), hepatitis B virus and retroelements by cytidine deamination on single-stranded DNA or by RNA binding. Here we report the high-resolution crystal structure of the carboxy-terminal deaminase domain of APOBEC3G (APOBEC3G-CD2) purified from Escherichia coli. The APOBEC3G-CD2 structure has a five-stranded beta-sheet core that is common to all known deaminase structures and closely resembles the structure of another APOBEC protein, APOBEC2 (ref. 5). A comparison of APOBEC3G-CD2 with other deaminase structures shows a structural conservation of the active-site loops that are directly involved in substrate binding. In the X-ray structure, these APOBEC3G active-site loops form a continuous 'substrate groove' around the active centre. The orientation of this putative substrate groove differs markedly (by 90 degrees) from the groove predicted by the NMR structure. We have introduced mutations around the groove, and have identified residues involved in substrate specificity, single-stranded DNA binding and deaminase activity. These results provide a basis for understanding the underlying mechanisms of substrate specificity for the APOBEC family.
Crystal structure of the anti-viral APOBEC3G catalytic domain and functional implications.,Holden LG, Prochnow C, Chang YP, Bransteitter R, Chelico L, Sen U, Stevens RC, Goodman MF, Chen XS Nature. 2008 Nov 6;456(7218):121-4. Epub 2008 Oct 12. PMID:18849968[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:http://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
- ↑ Holden LG, Prochnow C, Chang YP, Bransteitter R, Chelico L, Sen U, Stevens RC, Goodman MF, Chen XS. Crystal structure of the anti-viral APOBEC3G catalytic domain and functional implications. Nature. 2008 Nov 6;456(7218):121-4. Epub 2008 Oct 12. PMID:18849968 doi:10.1038/nature07357
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