Structural Determinants of the APOBEC3G N-Terminal Domain for HIV-1 RNA Association

Overview

Journal Front Cell Infect Microbiol

Specialties Cell Biology
Infectious Diseases
Microbiology

Date 2019 Jun 6

PMID 31165049

Citations 7

Authors

Hirofumi Fukuda

Songling Li

Luca Sardo

Jessica L Smith

Kazuo Yamashita

Anamaria D Sarca

Kotaro Shirakawa

Daron M Standley

Akifumi Takaori-Kondo

Taisuke Izumi

Affiliations

Soon will be listed here.

Abstract

APOBEC3G (A3G) is a cellular protein that inhibits HIV-1 infection through virion incorporation. The interaction of the A3G N-terminal domain (NTD) with RNA is essential for A3G incorporation in the HIV-1 virion. The interaction between A3G-NTD and RNA is not completely understood. The A3G-NTD is also recognized by HIV-1 Viral infectivity factor (Vif) and A3G-Vif binding leads to A3G degradation. Therefore, the A3G-Vif interaction is a target for the development of antiviral therapies that block HIV-1 replication. However, targeting the A3G-Vif interactions could disrupt the A3G-RNA interactions that are required for A3G's antiviral activity. To better understand A3G-RNA binding, we generated o docking models to simulate the RNA-binding propensity of A3G-NTD. We simulated the A3G-NTD residues with high RNA-binding propensity, experimentally validated our prediction by testing A3G-NTD mutations, and identified structural determinants of A3G-RNA binding. In addition, we found a novel amino acid residue, I26 responsible for RNA interaction. The new structural insights provided here will facilitate the design of pharmaceuticals that inhibit A3G-Vif interactions without negatively impacting A3G-RNA interactions.

Citing Articles

Molecular mechanism for regulating APOBEC3G DNA editing function by the non-catalytic domain.

Yang H, Pacheco J, Kim K, Bokani A, Ito F, Ebrahimi D Nat Commun. 2024; 15(1):8773.

PMID: 39389938 PMC: 11467180. DOI: 10.1038/s41467-024-52671-1.

Synthesis, characterization, computational analyses, in silico ADMET studies, and inhibitory action against SARS-CoV-2 main protease (Mpro) of a Schiff base.

Sahin S, Dege N Turk J Chem. 2023; 46(5):1548-1564.

PMID: 37529731 PMC: 10390206. DOI: 10.55730/1300-0527.3460.

Insights Into Persistent HIV-1 Infection and Functional Cure: Novel Capabilities and Strategies.

Ta T, Malik S, Anderson E, Jones A, Perchik J, Freylikh M Front Microbiol. 2022; 13:862270.

PMID: 35572626 PMC: 9093714. DOI: 10.3389/fmicb.2022.862270.

Characterization of an A3G-Vif-CRL5-CBFβ Structure Using a Cross-linking Mass Spectrometry Pipeline for Integrative Modeling of Host-Pathogen Complexes.

Kaake R, Echeverria I, Kim S, Von Dollen J, Chesarino N, Feng Y Mol Cell Proteomics. 2021; 20:100132.

PMID: 34389466 PMC: 8459920. DOI: 10.1016/j.mcpro.2021.100132.

FRET-Based Detection and Quantification of HIV-1 Virion Maturation.

Sarca A, Sardo L, Fukuda H, Matsui H, Shirakawa K, Horikawa K Front Microbiol. 2021; 12:647452.

PMID: 33767685 PMC: 7985248. DOI: 10.3389/fmicb.2021.647452.

References

Friew Y, Boyko V, Hu W, Pathak V . Intracellular interactions between APOBEC3G, RNA, and HIV-1 Gag: APOBEC3G multimerization is dependent on its association with RNA. Retrovirology. 2009; 6:56. PMC: 2700067. DOI: 10.1186/1742-4690-6-56. View

Luo K, Liu B, Xiao Z, Yu Y, Yu X, Gorelick R . Amino-terminal region of the human immunodeficiency virus type 1 nucleocapsid is required for human APOBEC3G packaging. J Virol. 2004; 78(21):11841-52. PMC: 523292. DOI: 10.1128/JVI.78.21.11841-11852.2004. View

Schumacher A, Hache G, MacDuff D, Brown W, Harris R . The DNA deaminase activity of human APOBEC3G is required for Ty1, MusD, and human immunodeficiency virus type 1 restriction. J Virol. 2008; 82(6):2652-60. PMC: 2259018. DOI: 10.1128/JVI.02391-07. View

Gorle S, Pan Y, Sun Z, Shlyakhtenko L, Harris R, Lyubchenko Y . Computational Model and Dynamics of Monomeric Full-Length APOBEC3G. ACS Cent Sci. 2017; 3(11):1180-1188. PMC: 5704289. DOI: 10.1021/acscentsci.7b00346. View

Matume N, Tebit D, Gray L, Turner S, Rekosh D, Bessong P . Characterization of APOBEC3 variation in a population of HIV-1 infected individuals in northern South Africa. BMC Med Genet. 2019; 20(1):21. PMC: 6339282. DOI: 10.1186/s12881-018-0740-4. View

Izumi T, Shirakawa K, Takaori-Kondo A . Cytidine deaminases as a weapon against retroviruses and a new target for antiviral therapy. Mini Rev Med Chem. 2008; 8(3):231-8. DOI: 10.2174/138955708783744047. View

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

Izumi T, Takaori-Kondo A, Shirakawa K, Higashitsuji H, Itoh K, Io K . MDM2 is a novel E3 ligase for HIV-1 Vif. Retrovirology. 2009; 6:1. PMC: 2629459. DOI: 10.1186/1742-4690-6-1. View

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

10.

Wang T, Tian C, Zhang W, Luo K, Sarkis P, Yu L . 7SL RNA mediates virion packaging of the antiviral cytidine deaminase APOBEC3G. J Virol. 2007; 81(23):13112-24. PMC: 2169093. DOI: 10.1128/JVI.00892-07. View

11.

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

12.

Huthoff H, Malim M . Identification of amino acid residues in APOBEC3G required for regulation by human immunodeficiency virus type 1 Vif and Virion encapsidation. J Virol. 2007; 81(8):3807-15. PMC: 1866099. DOI: 10.1128/JVI.02795-06. View

13.

Chen J, Nikolaitchik O, Singh J, Wright A, Bencsics C, Coffin J . High efficiency of HIV-1 genomic RNA packaging and heterozygote formation revealed by single virion analysis. Proc Natl Acad Sci U S A. 2009; 106(32):13535-40. PMC: 2714765. DOI: 10.1073/pnas.0906822106. View

14.

Burdick R, Smith J, Chaipan C, Friew Y, Chen J, Venkatachari N . P body-associated protein Mov10 inhibits HIV-1 replication at multiple stages. J Virol. 2010; 84(19):10241-53. PMC: 2937795. DOI: 10.1128/JVI.00585-10. View

15.

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

16.

Stopak K, de Noronha C, Yonemoto W, Greene W . HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability. Mol Cell. 2003; 12(3):591-601. DOI: 10.1016/s1097-2765(03)00353-8. View

17.

Zhai C, Ma L, Zhang Z, Ding J, Wang J, Zhang Y . Identification and characterization of loop7 motif and its role in regulating biological function of human APOBEC3G through molecular modeling and biological assay. Acta Pharm Sin B. 2017; 7(5):571-582. PMC: 5595295. DOI: 10.1016/j.apsb.2017.05.002. View

18.

Guerrero S, Libre C, Batisse J, Mercenne G, Richer D, Laumond G . Translational regulation of APOBEC3G mRNA by Vif requires its 5'UTR and contributes to restoring HIV-1 infectivity. Sci Rep. 2016; 6:39507. PMC: 5171582. DOI: 10.1038/srep39507. View

19.

Belanger K, Savoie M, Gerpe M, Couture J, Langlois M . Binding of RNA by APOBEC3G controls deamination-independent restriction of retroviruses. Nucleic Acids Res. 2013; 41(15):7438-52. PMC: 3753645. DOI: 10.1093/nar/gkt527. View

20.

Harris R, Bishop K, Sheehy A, Craig H, Petersen-Mahrt S, Watt I . DNA deamination mediates innate immunity to retroviral infection. Cell. 2003; 113(6):803-9. DOI: 10.1016/s0092-8674(03)00423-9. View