Nucleic Acids Research Advance Access originally published online on October 16, 2007
Nucleic Acids Research 2007 35(21):7096-7108; doi:10.1093/nar/gkm750
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Nucleic Acids Research, 2007, Vol. 35, No. 21 7096-7108
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Deaminase-independent inhibition of HIV-1 reverse transcription by APOBEC3G
1Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA, 2AIDS Research Center, National Institute of Infectious Diseases, Tokyo 208-0013, Japan, 3Department of Structural Biology, University of Pittsburgh Medical School, Pittsburgh, PA 15260, 4Department of Physics, Northeastern University, Boston, MA 02115, 5Department of Chemistry, 6Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455 and 7Department of Chemistry and Department of Biochemistry, Ohio State University, Columbus, OH 43210, USA
* To whom correspondence should be addressed. Tel: +1 301 496 1970; Fax: +1 301 496 0243; Email: levinju{at}mail.nih.gov
Received August 7, 2007. Revised September 10, 2007. Accepted September 10, 2007.
APOBEC3G (A3G), a host protein that inhibits HIV-1 reverse transcription and replication in the absence of Vif, displays cytidine deaminase and single-stranded (ss) nucleic acid binding activities. HIV-1 nucleocapsid protein (NC) also binds nucleic acids and has a unique property, nucleic acid chaperone activity, which is crucial for efficient reverse transcription. Here we report the interplay between A3G, NC and reverse transcriptase (RT) and the effect of highly purified A3G on individual reactions that occur during reverse transcription. We find that A3G did not affect the kinetics of NC-mediated annealing reactions, nor did it inhibit RNase H cleavage. In sharp contrast, A3G significantly inhibited all RT-catalyzed DNA elongation reactions with or without NC. In the case of (–) strong-stop DNA synthesis, the inhibition was independent of A3G's catalytic activity. Fluorescence anisotropy and single molecule DNA stretching analyses indicated that NC has a higher nucleic acid binding affinity than A3G, but more importantly, displays faster association/disassociation kinetics. RT binds to ssDNA with a much lower affinity than either NC or A3G. These data support a novel mechanism for deaminase-independent inhibition of reverse transcription that is determined by critical differences in the nucleic acid binding properties of A3G, NC and RT.
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