Mutational Comparison of the Single-domained APOBEC3C and Double-domained APOBEC3F/G Anti-retroviral Cytidine Deaminases Provides Insight into Their DNA Target Site Specificities

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2005 Apr 6

PMID 15809227

Citations 126

Authors

Marc-Andre Langlois

Rupert C L Beale

Silvestro G Conticello

Michael S Neuberger

Affiliations

Soon will be listed here.

Abstract

Human APOBEC3F and APOBEC3G are double-domained deaminases that can catalyze dC-->dU deamination in HIV-1 and MLV retroviral DNA replication intermediates, targeting T-C or C-C dinucleotides, respectively. HIV-1 antagonizes their action through its vif gene product, which has been shown (at least in the case of APOBEC3G) to interact with the N-terminal domain of the deaminase, triggering its degradation. Here, we compare APOBEC3F and APOBEC3G to APOBEC3C, a single-domained deaminase that can also act on both HIV-1 and MLV. We find that whereas APOBEC3C contains all the information necessary for both Vif-binding and cytidine deaminase activity in a single domain, it is the C-terminal domain of APOBEC3F and APOBEC3G that confer their target site specificity for cytidine deamination. We have exploited the fact that APOBEC3C, whilst highly homologous to the C-terminal domain of APOBEC3F, exhibits a distinct target site specificity (preferring Y-C dinucleotides) in order to identify residues in APOBEC3F that might affect its target site specificity. We find that this specificity can be altered by single amino acid substitutions at several distinct positions, suggesting that the strong dependence of APOBEC3-mediated deoxycytidine deamination on the 5'-flanking nucleotide is sensitive to relatively subtle changes in the APOBEC3 structure. The approach has allowed the isolation of APOBEC3 DNA mutators that exhibit novel target site preferences.

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References

Noguchi C, Ishino H, Tsuge M, Fujimoto Y, Imamura M, Takahashi S . G to A hypermutation of hepatitis B virus. Hepatology. 2005; 41(3):626-33. DOI: 10.1002/hep.20580. View

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; 278(45):44412-6. DOI: 10.1074/jbc.C300376200. View

Sheehy A, Gaddis N, Malim M . The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif. Nat Med. 2003; 9(11):1404-7. DOI: 10.1038/nm945. View

Marin M, Rose K, Kozak S, Kabat D . HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation. Nat Med. 2003; 9(11):1398-403. DOI: 10.1038/nm946. View

Yu X, Yu Y, Liu B, Luo K, Kong W, Mao P . Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex. Science. 2003; 302(5647):1056-60. DOI: 10.1126/science.1089591. View

Conticello S, Harris R, Neuberger M . The Vif protein of HIV triggers degradation of the human antiretroviral DNA deaminase APOBEC3G. Curr Biol. 2003; 13(22):2009-13. DOI: 10.1016/j.cub.2003.10.034. View

Beale R, Petersen-Mahrt S, Watt I, Harris R, Rada C, Neuberger M . Comparison of the differential context-dependence of DNA deamination by APOBEC enzymes: correlation with mutation spectra in vivo. J Mol Biol. 2004; 337(3):585-96. DOI: 10.1016/j.jmb.2004.01.046. View

Schrofelbauer B, Chen D, Landau N . A single amino acid of APOBEC3G controls its species-specific interaction with virion infectivity factor (Vif). Proc Natl Acad Sci U S A. 2004; 101(11):3927-32. PMC: 374346. DOI: 10.1073/pnas.0307132101. View

Bogerd H, Doehle B, Wiegand H, Cullen B . A single amino acid difference in the host APOBEC3G protein controls the primate species specificity of HIV type 1 virion infectivity factor. Proc Natl Acad Sci U S A. 2004; 101(11):3770-4. PMC: 374319. DOI: 10.1073/pnas.0307713101. View

10.

Turelli P, Mangeat B, Jost S, Vianin S, Trono D . Inhibition of hepatitis B virus replication by APOBEC3G. Science. 2004; 303(5665):1829. DOI: 10.1126/science.1092066. View

11.

Mangeat B, Turelli P, Liao S, Trono D . A single amino acid determinant governs the species-specific sensitivity of APOBEC3G to Vif action. J Biol Chem. 2004; 279(15):14481-3. DOI: 10.1074/jbc.C400060200. View

12.

Xu H, Svarovskaia E, Barr R, Zhang Y, Khan M, Strebel K . A single amino acid substitution in human APOBEC3G antiretroviral enzyme confers resistance to HIV-1 virion infectivity factor-induced depletion. Proc Natl Acad Sci U S A. 2004; 101(15):5652-7. PMC: 397464. DOI: 10.1073/pnas.0400830101. View

13.

Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T . Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell. 2000; 102(5):553-63. DOI: 10.1016/s0092-8674(00)00078-7. View

14.

Janini M, Rogers M, Birx D, McCutchan F . Human immunodeficiency virus type 1 DNA sequences genetically damaged by hypermutation are often abundant in patient peripheral blood mononuclear cells and may be generated during near-simultaneous infection and activation of CD4(+) T cells. J Virol. 2001; 75(17):7973-86. PMC: 115041. DOI: 10.1128/jvi.75.17.7973-7986.2001. View

15.

Ireton G, McDermott G, Black M, Stoddard B . The structure of Escherichia coli cytosine deaminase. J Mol Biol. 2002; 315(4):687-97. DOI: 10.1006/jmbi.2001.5277. View

16.

Martin A, Bardwell P, Woo C, Fan M, Shulman M, Scharff M . Activation-induced cytidine deaminase turns on somatic hypermutation in hybridomas. Nature. 2002; 415(6873):802-6. DOI: 10.1038/nature714. View

17.

Jarmuz A, Chester A, Bayliss J, Gisbourne J, Dunham I, Scott J . An anthropoid-specific locus of orphan C to U RNA-editing enzymes on chromosome 22. Genomics. 2002; 79(3):285-96. DOI: 10.1006/geno.2002.6718. View

18.

Vartanian J, Henry M, Wain-Hobson S . Sustained G-->A hypermutation during reverse transcription of an entire human immunodeficiency virus type 1 strain Vau group O genome. J Gen Virol. 2002; 83(Pt 4):801-805. DOI: 10.1099/0022-1317-83-4-801. View

19.

Demaison C, Parsley K, Brouns G, Scherr M, Battmer K, Kinnon C . High-level transduction and gene expression in hematopoietic repopulating cells using a human immunodeficiency [correction of imunodeficiency] virus type 1-based lentiviral vector containing an internal spleen focus forming virus promoter. Hum Gene Ther. 2002; 13(7):803-13. DOI: 10.1089/10430340252898984. View

20.

Sheehy A, Gaddis N, Choi J, Malim M . Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature. 2002; 418(6898):646-50. DOI: 10.1038/nature00939. View