Abstract
The human apolipoprotein B mRNA-editing enzyme catalytic polypeptide–like 3 (APOBEC3, referred to as A3) proteins are cellular cytidine deaminases that potently restrict retrovirus replication. However, HIV-1 viral infectivity factor (Vif) counteracts the antiviral activity of most A3 proteins by targeting them for proteasomal degradation. To date, the structure of an A3 protein containing a Vif-binding interface has not been solved. Here, we report a high-resolution crystal structure of APOBEC3C and identify the HIV-1 Vif–interaction interface. Extensive structure-guided mutagenesis revealed the role of a shallow cavity composed of hydrophobic or negatively charged residues between the α2 and α3 helices. This region is distant from the DPD motif (residues 128–130) of APOBEC3G that participates in HIV-1 Vif interaction. These findings provide insight into Vif-A3 interactions and could lead to the development of new pharmacologic anti–HIV-1 compounds.
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Acknowledgements
We thank A.M. Gronenborn, J.G. Levin and K. Strebel for critical discussions and reading of the manuscript. We also thank K. Tokunaga (National Institute of Infectious Diseases, Tokyo, Japan) for providing the pCAGGS APOBEC3 plasmids. This work was supported in part by a grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan to Y.I. (JSPS KAKENHI 24590568) and by a grant for HIV/AIDS research from the Ministry of Health, Labor and Welfare of Japan to Y.I.
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S.K., H.O., M.N., T.K., T.Y., N.W., A.S. and Y.I. performed experiments and analysis for the crystal structure determination; S.K., M.N., M.I., Y.N., T.K., Y.Y. and Y.I. performed biochemical experiments; S.K., M.N., M.I., Y.N., Y.Y., W.S. and Y.I. analyzed the biochemical data; Y.I. directed the project; S.K., H.O. and Y.I. wrote the manuscript with all authors' help.
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Kitamura, S., Ode, H., Nakashima, M. et al. The APOBEC3C crystal structure and the interface for HIV-1 Vif binding. Nat Struct Mol Biol 19, 1005–1010 (2012). https://doi.org/10.1038/nsmb.2378
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DOI: https://doi.org/10.1038/nsmb.2378
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