| Structural highlights
Function
[ABC3F_HUMAN] DNA deaminase (cytidine deaminase) which acts as an inhibitor of retrovirus replication and retrotransposon mobility via deaminase-dependent and -independent mechanisms. Exhibits antiviral activity against vif-deficient HIV-1. After the penetration of retroviral nucleocapsids into target cells of infection and the initiation of reverse transcription, it can induce the conversion of cytosine to uracil in the minus-sense single-strand viral DNA, leading to G-to-A hypermutations in the subsequent plus-strand viral DNA. The resultant detrimental levels of mutations in the proviral genome, along with a deamination-independent mechanism that works prior to the proviral integration, together exert efficient antiretroviral effects in infected target cells. Selectively targets single-stranded DNA and does not deaminate double-stranded DNA or single- or double-stranded RNA. Exhibits antiviral activity also against hepatitis B virus (HBV), equine infectious anemia virus (EIAV), xenotropic MuLV-related virus (XMRV) and simian foamy virus (SFV) and may inhibit the mobility of LTR and non-LTR retrotransposons. May also play a role in the epigenetic regulation of gene expression through the process of active DNA demethylation.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Publication Abstract from PubMed
The APOBEC3 family of DNA cytosine deaminases is capable of restricting the replication of HIV-1 and other pathogens. Here, we report a 1.92 A resolution crystal structure of the Vif-binding and catalytic domain of APOBEC3F (A3F). This structure is distinct from the previously published APOBEC and phylogenetically related deaminase structures, as it is the first without zinc in the active site. We determined an additional structure containing zinc in the same crystal form that allows direct comparison with the zinc-free structure. In the absence of zinc, the conserved active site residues that normally participate in zinc coordination show unique conformations, including a 90 degree rotation of His249 and disulfide bond formation between Cys280 and Cys283. We found that zinc coordination is influenced by pH, and treating the protein at low pH in crystallization buffer is sufficient to remove zinc. Zinc coordination and catalytic activity are reconstituted with the addition of zinc only in a reduced environment likely due to the two active site cysteines readily forming a disulfide bond when not coordinating zinc. We show that the enzyme is active in the presence of zinc and cobalt but not with other divalent metals. These results unexpectedly demonstrate that zinc is not required for the structural integrity of A3F and suggest that metal coordination may be a strategy for regulating the activity of A3F and related deaminases.
1.92 Angstrom Zinc-Free APOBEC3F Catalytic Domain Crystal Structure.,Shaban NM, Shi K, Li M, Aihara H, Harris RS J Mol Biol. 2016 Jun 5;428(11):2307-16. doi: 10.1016/j.jmb.2016.04.026. Epub 2016, Apr 30. PMID:27139641[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wiegand HL, Doehle BP, Bogerd HP, Cullen BR. A second human antiretroviral factor, APOBEC3F, is suppressed by the HIV-1 and HIV-2 Vif proteins. EMBO J. 2004 Jun 16;23(12):2451-8. Epub 2004 May 20. PMID:15152192 doi:10.1038/sj.emboj.7600246
- ↑ 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
- ↑ Delebecque F, Suspene R, Calattini S, Casartelli N, Saib A, Froment A, Wain-Hobson S, Gessain A, Vartanian JP, Schwartz O. Restriction of foamy viruses by APOBEC cytidine deaminases. J Virol. 2006 Jan;80(2):605-14. PMID:16378963 doi:10.1128/JVI.80.2.605-614.2006
- ↑ Zielonka J, Bravo IG, Marino D, Conrad E, Perkovic M, Battenberg M, Cichutek K, Munk C. Restriction of equine infectious anemia virus by equine APOBEC3 cytidine deaminases. J Virol. 2009 Aug;83(15):7547-59. doi: 10.1128/JVI.00015-09. Epub 2009 May 20. PMID:19458006 doi:10.1128/JVI.00015-09
- ↑ Mbisa JL, Bu W, Pathak VK. APOBEC3F and APOBEC3G inhibit HIV-1 DNA integration by different mechanisms. J Virol. 2010 May;84(10):5250-9. doi: 10.1128/JVI.02358-09. Epub 2010 Mar 10. PMID:20219927 doi:10.1128/JVI.02358-09
- ↑ Paprotka T, Venkatachari NJ, Chaipan C, Burdick R, Delviks-Frankenberry KA, Hu WS, Pathak VK. Inhibition of xenotropic murine leukemia virus-related virus by APOBEC3 proteins and antiviral drugs. J Virol. 2010 Jun;84(11):5719-29. doi: 10.1128/JVI.00134-10. Epub 2010 Mar 24. PMID:20335265 doi:10.1128/JVI.00134-10
- ↑ Stenglein MD, Burns MB, Li M, Lengyel J, Harris RS. APOBEC3 proteins mediate the clearance of foreign DNA from human cells. Nat Struct Mol Biol. 2010 Feb;17(2):222-9. doi: 10.1038/nsmb.1744. Epub 2010 Jan , 10. PMID:20062055 doi:10.1038/nsmb.1744
- ↑ Guo JU, Su Y, Zhong C, Ming GL, Song H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell. 2011 Apr 29;145(3):423-34. doi: 10.1016/j.cell.2011.03.022. Epub 2011 Apr, 14. PMID:21496894 doi:10.1016/j.cell.2011.03.022
- ↑ Hultquist JF, Lengyel JA, Refsland EW, LaRue RS, Lackey L, Brown WL, Harris RS. Human and rhesus APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H demonstrate a conserved capacity to restrict Vif-deficient HIV-1. J Virol. 2011 Nov;85(21):11220-34. doi: 10.1128/JVI.05238-11. Epub 2011 Aug 10. PMID:21835787 doi:10.1128/JVI.05238-11
- ↑ Phalora PK, Sherer NM, Wolinsky SM, Swanson CM, Malim MH. HIV-1 replication and APOBEC3 antiviral activity are not regulated by P bodies. J Virol. 2012 Nov;86(21):11712-24. doi: 10.1128/JVI.00595-12. Epub 2012 Aug 22. PMID:22915799 doi:10.1128/JVI.00595-12
- ↑ Refsland EW, Hultquist JF, Harris RS. Endogenous origins of HIV-1 G-to-A hypermutation and restriction in the nonpermissive T cell line CEM2n. PLoS Pathog. 2012;8(7):e1002800. doi: 10.1371/journal.ppat.1002800. Epub 2012 Jul, 12. PMID:22807680 doi:10.1371/journal.ppat.1002800
- ↑ Chaipan C, Smith JL, Hu WS, Pathak VK. APOBEC3G restricts HIV-1 to a greater extent than APOBEC3F and APOBEC3DE in human primary CD4+ T cells and macrophages. J Virol. 2013 Jan;87(1):444-53. doi: 10.1128/JVI.00676-12. Epub 2012 Oct 24. PMID:23097438 doi:10.1128/JVI.00676-12
- ↑ Gillick K, Pollpeter D, Phalora P, Kim EY, Wolinsky SM, Malim MH. Suppression of HIV-1 infection by APOBEC3 proteins in primary human CD4(+) T cells is associated with inhibition of processive reverse transcription as well as excessive cytidine deamination. J Virol. 2013 Feb;87(3):1508-17. doi: 10.1128/JVI.02587-12. Epub 2012 Nov 14. PMID:23152537 doi:10.1128/JVI.02587-12
- ↑ Shaban NM, Shi K, Li M, Aihara H, Harris RS. 1.92 Angstrom Zinc-Free APOBEC3F Catalytic Domain Crystal Structure. J Mol Biol. 2016 Jun 5;428(11):2307-16. doi: 10.1016/j.jmb.2016.04.026. Epub 2016, Apr 30. PMID:27139641 doi:http://dx.doi.org/10.1016/j.jmb.2016.04.026
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