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Nucleic Acids Research 2005 33(6):1913-1923; doi:10.1093/nar/gki343
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Published online 4 April 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oupjournals.org

Article

Mutational comparison of the single-domained APOBEC3C and double-domained APOBEC3F/G anti-retroviral cytidine deaminases provides insight into their DNA target site specificities

Marc-André Langlois, Rupert C. L. Beale, Silvestro G. Conticello and Michael S. Neuberger*

Medical Research Council Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry Hills Road, Cambridge CB2 2QH, UK

*To whom correspondence should be addressed. Tel: +44 1223 402269; Fax: +44 1223 412178; Email: msn{at}mrc-lmb.cam.ac.uk

Received January 6, 2005. Revised March 18, 2005. Accepted March 18, 2005.

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.

Correspondence may also be addressed to Marc-André Langlois. Tel: +44 1223 402269; Fax: +44 1223 412178; Email: mal{at}mrc-lmb.cam.ac.uk

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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