APOBEC3G Subunits Self-associate via the C-terminal Deaminase Domain

Bennett, Ryan P.; Salter, Jason D.; Liu, Xiang; Wedekind, Joseph E.; Smith, Harold C.

doi:10.1074/jbc.m803726200

Cited by 44 publications

(51 citation statements)

References 66 publications

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“…A3F and A3G have been shown to hetero-oligomerize on RNA in an RNA-dependent manner (47). However, A3F and A3G can also form homo-oligomers in the absence of RNA (38,48,49). Here, we examined if A3F and A3G could also form hetero-oligomers in the absence of RNA.…”

Section: Resultsmentioning

confidence: 99%

Mechanism of Enhanced HIV Restriction by Virion Coencapsidated Cytidine Deaminases APOBEC3F and APOBEC3G

Ara

Love

Follack

et al. 2017

J Virol

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The APOBEC3 (A3) enzymes, A3G and A3F, are coordinately expressed in CD4 ϩ T cells and can become coencapsidated into HIV-1 virions, primarily in the absence of the viral infectivity factor (Vif). A3F and A3G are deoxycytidine deaminases that inhibit HIV-1 replication by inducing guanine-to-adenine hypermutation through deamination of cytosine to form uracil in minus-strand DNA. The effect of the simultaneous presence of both A3G and A3F on HIV-1 restriction ability is not clear. Here, we used a single-cycle infectivity assay and biochemical analyses to determine if coencapsidated A3G and A3F differ in their restriction capacity from A3G or A3F alone. Proviral DNA sequencing demonstrated that compared to each A3 enzyme alone, A3G and A3F, when combined, had a coordinate effect on hypermutation. Using size exclusion chromatography, rotational anisotropy, and in vitro deamination assays, we demonstrate that A3F promotes A3G deamination activity by forming an A3F/G hetero-oligomer in the absence of RNA which is more efficient at deaminating cytosines. Further, A3F caused the accumulation of shorter reverse transcripts due to decreasing reverse transcriptase efficiency, which would leave singlestranded minus-strand DNA exposed for longer periods of time, enabling more deamination events to occur. Although A3G and A3F are known to function alongside each other, these data provide evidence for an A3F/G hetero-oligomeric A3 with unique properties compared to each individual counterpart.IMPORTANCE The APOBEC3 enzymes APOBEC3F and APOBEC3G act as a barrier to HIV-1 replication in the absence of the HIV-1 Vif protein. After APOBEC3 enzymes are encapsidated into virions, they deaminate cytosines in minus-strand DNA, which forms promutagenic uracils that induce transition mutations or proviral DNA degradation. Even in the presence of Vif, footprints of APOBEC3-catalyzed deaminations are found, demonstrating that APOBEC3s still have discernible activity against HIV-1 in infected individuals. We undertook a study to better understand the activity of coexpressed APOBEC3F and APOBEC3G. The data demonstrate that an APOBEC3F/ APOBEC3G hetero-oligomer can form that has unique properties compared to each APOBEC3 alone. This hetero-oligomer has increased efficiency of virus hypermutation, raising the idea that we still may not fully realize the antiviral mechanisms of endogenous APOBEC3 enzymes. Hetero-oligomerization may be a mechanism to increase their antiviral activity in the presence of Vif.

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Section: Resultsmentioning

confidence: 99%

Mechanism of Enhanced HIV Restriction by Virion Coencapsidated Cytidine Deaminases APOBEC3F and APOBEC3G

Ara

Love

Follack

et al. 2017

J Virol

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“…This model implied that the full-length A3G in either low molecular mass or high molecular mass is symmetrically associated (51). This model was further refined into the fourth model after the A3G-CD2 three-dimensional structure was reported, through an in-cell quenched fluorescence resonance energy transfer (FRET) assay, small angle x-ray scattering, and other techniques (52). In this model, A3G was self-associated via its CD2 domain, forming a dimer structure.…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure of DNA Cytidine Deaminase ABOBEC3G Catalytic Deamination Domain Suggests a Binding Mode of Full-length Enzyme to Single-stranded DNA

Zhang

et al. 2015

Journal of Biological Chemistry

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Background:The mechanism for DNA cytidine deaminase APOBEC3G (A3G) interacting with single-stranded DNA (ssDNA) is not well characterized. Results: The crystal structure of a head-to-tail dimer of the A3G catalytic deamination domain (A3G-CD2) was obtained. Conclusion:The dimer structure of A3G-CD2 suggests a binding mode of full-length A3G to ssDNA. Significance: The dimer structure of A3G-CD2 may represent a structural model of full-length A3G.

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“…How Apo3G monomers interact with each during dimerization also remains controversial. Bennett et al propose that Apo3G forms dimers via interactions of the CD2 domain that are independent of RNA [105]. Based on Fret and co-immunoprecipitation experiments, Bennett et al show that the truncated Apo3G-CD1 proteins do not self associate, while the truncated Apo3G-CD2 proteins do [105].…”

Section: Structural Insights For the Inactive Apo3g Cd1 And Apo3g Olimentioning

confidence: 99%

The current structural and functional understanding of APOBEC deaminases

Bransteitter

Prochnow

Chen

2009

Cell. Mol. Life Sci.

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The apolipoprotein B mRNA-editing enzyme catalytic polypeptide (APOBEC) family of cytidine deaminases has emerged as an intensively studied field as a result of their important biological functions. These enzymes are involved in lipid metabolism, antibody diversification, and the inhibition of retrotransposons, retroviruses, and some DNA viruses. The APOBEC proteins function in these roles by deaminating single-stranded (ss) DNA or RNA. There are two high-resolution crystal structures available for the APOBEC family, Apo2 and the C-terminal catalytic domain (CD2) of Apo3G or Apo3G-CD2 [Holden et al. (Nature 456:121-124, 2008); Prochnow et al. (Nature 445:447-451, 2007)]. Additionally, the structure of Apo3G-CD2 has also been determined using NMR [Chen et al. (Nature 452:116-119, 2008); Furukawa et al. (EMBO J 28:440-451, 2009); Harjes et al. (J Mol Biol, 2009)]. A detailed structural analysis of the APOBEC proteins and a comparison to other zinc-coordinating deaminases can facilitate our understanding of how APOBEC proteins bind nucleic acids, recognize substrates, and form oligomers. Here, we review the recent development of structural and functional studies that apply to Apo3G as well as the APOBEC deaminase family.

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APOBEC3G Subunits Self-associate via the C-terminal Deaminase Domain

Cited by 44 publications

References 66 publications

Mechanism of Enhanced HIV Restriction by Virion Coencapsidated Cytidine Deaminases APOBEC3F and APOBEC3G

Mechanism of Enhanced HIV Restriction by Virion Coencapsidated Cytidine Deaminases APOBEC3F and APOBEC3G

Crystal Structure of DNA Cytidine Deaminase ABOBEC3G Catalytic Deamination Domain Suggests a Binding Mode of Full-length Enzyme to Single-stranded DNA

The current structural and functional understanding of APOBEC deaminases

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