APOBEC3G
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APOBEC3G (apolipoprotein B mRNA editing enzyme, catalytic subunit 3G) is a human
APOBEC3G exerts innate
Discovery
It was first identified by Jarmuz et al.[15] as a member of family of proteins APOBEC3A to 3G on chromosome 22 in 2002 and later also as a cellular factor able to restrict replication of HIV-1 lacking the viral accessory protein Vif. Soon after, it was shown that APOBEC3G belonged to a family of proteins grouped together due to their homology with the cytidine deaminase APOBEC1.
Structure
APOBEC3G has a symmetric structure, resulting in 2 homologous
coordination site.[16] Each domain also has the typical His/Cys-X-Glu-X23–28-Pro-Cys-X2-Cys motif for cytidine deaminases. However, unlike the typical cytidine deaminases, APOBEC3G contains a unique alpha helix between two beta sheets in the catalytic domain that could be a cofactor binding site.[17]
CD2 is catalytically active and vital for deamination and motif specificity. CD1 is catalytically inactive, but very important for binding to DNA and RNA and is key to defining the 5’->3’ processivity of APOBEC3G deamination.[18] CD2 has no deaminase activity without the presence of CD1.[19]
Native APOBEC3G is composed of
The D128 amino acid residue, which lies within CD1 (Figure 1), appears to be particularly important for APOBEC3G interactions with Vif because a D128K point mutation prevents Vif-dependent depletion of APOBEC3G.[20][21] Additionally, amino acids 128–130 on APOBEC3G form a negatively charged motif that is critical for interactions with Vif and the formation of APOBEC3G-Vif complexes. Furthermore, residues 124-127 are important for encapsidation of APOBEC3G into HIV-1 virions and the resulting antiretroviral activity.[22]
Mechanism of action
APOBEC3G has been widely studied and several mechanisms that negatively affect HIV-1 replication have been identified.
Cytidine deamination and hypermutation
APOBEC3G and other proteins in the same family are able to act as
The deamination activity ultimately results in G→A hypermutations at “hot spots” of the proviral DNA. Such hypermutation ultimately destroys the coding and replicative capacity of the virus, resulting in many nonviable virions.[12][25] APOBEC3G has a much weaker antiviral effect when its active site has been mutated to the point that the protein can no longer mutate retroviral DNA.[26] It was originally thought that the APOBEC3G-mediated deamination can also indirectly lead to viral DNA degradation by DNA repair systems attracted to the mutated residues.[27] However, this has been discounted because human APOBEC3G reduces viral cDNA levels independently of DNA repair enzymes UNG and SMUG1.[28]
Interference with reverse transcription
APOBEC3G interferes with reverse transcription of HIV-1 independent of DNA deamination.
Interference with viral DNA integration
APOBEC3G was associated with interference of viral DNA integration into the host genome in a manner dependent on functional catalytic domains and deaminase activity. Mbisa et al. saw that APOBEC3G interferes with the processing and removal of primer tRNA from the DNA minus strand, thus leading to aberrant viral 3’ long terminal repeat (LTR) DNA ends. These viral DNA ends are inefficient substrates for integration and plus-strand DNA transfer. As a result, HIV-1 provirus formation is inhibited.[23]
Biological function
HIV encapsidation
APOBEC3G mRNA is expressed in certain cells, referred to as non-permissive cells, in which HIV-1 cannot properly infect and replicate in the absence of Vif. Such cells include physiologically relevant primary
The amount that is incorporated into virions is dependent on the level of APOBEC3G expression within the cell producing the virion. Xu et al. conducted studies with
In addition to deterring replication of exogenous retroviruses, A3G also acts upon human endogenous retroviruses, leaving similar signatures of hypermutations in them.[32][33]
Disease relevance
APOBEC3G is expressed within the non-permissive cells and is a key inhibitory factor of HIV-1 replication and infectivity. However, Vif counteracts this antiretroviral factor, enabling production of viable and infective HIV-1 virions in the presence of APOBEC3G activity .[30][34] In particular, Vif prevents incorporation of APOBEC3G into HIV-1 virions and promotes destruction of the enzyme in a manner independent of all other HIV-1 proteins.[35]
While APOBEC3G has typically been studied as a vital protein exhibiting potent antiviral effects on HIV-1, recent studies have elucidated the potential of APOBEC3G-mediated mutation to help to facilitate the propagation HIV-1. The number of deaminations in the preferred regions varies from one to many, possibly dependent on the time of exposure to APOBEC3G.[25] Additionally, it has been shown that there is a dose response between intracellular APOBEC3G concentration and degree of viral hypermutation.[36] Some HIV-1 proviruses with APOBEC3G-mediated mutation have been shown to thrive because they carry too few mutations at APOBEC3G hotspots or because recombination between a lethally APOBEC3G-restricted provirus and a viable provirus has occurred.[37] Such sublethal mutagenesis contributes to greater genetic diversity among the HIV-1 virus population, demonstrating the potential for APOBEC3G to enhance HIV-1's ability to adapt and propagate.
References
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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- S2CID 4151961.
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- PMID 20152150.
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- PMID 19389408.
- PMID 22181350.
- ^ PMID 18499212.
- PMID 23760237.
- PMID 29769087.
- PMID 11863358.
- ^ PMID 18789977.
- PMID 15780864.
- ^ PMID 20212048.
- PMID 21489586.
- S2CID 1789911.
- PMID 15054139.
- PMID 17267497.
- ^ PMID 17428871.
- PMID 12826402.
- ^ PMID 20463080.
- PMID 18577210.
- ^ PMID 16971427.
- PMID 18272574.
- ^ PMID 18597677.
- ^ PMID 20538015.
- PMID 17126871.
- PMID 18562517.
- PMID 18562521.
- PMID 15383144.
- PMID 14527406.
- PMID 18339206.
- PMID 18391217.
External links
- Human APOBEC3G genome location and APOBEC3G gene details page in the UCSC Genome Browser.
Further reading
- Prochnow C, Bransteitter R, Klein MG, Goodman MF, Chen XS (January 2007). "The APOBEC-2 crystal structure and functional implications for the deaminase AID". Nature. 445 (7126): 447–51. S2CID 4394772.
- Iwabu Y, Kinomoto M, Tatsumi M, Fujita H, Shimura M, Tanaka Y, et al. (November 2010). "Differential anti-APOBEC3G activity of HIV-1 Vif proteins derived from different subtypes". The Journal of Biological Chemistry. 285 (46): 35350–8. PMID 20833716.