Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A, also known as APOBEC3A, or A3A is a
gene of the
APOBEC3 family found in humans, non-human
primates, and some other
mammals.[3] It is a single-domain
DNAcytidine deaminase with antiviral effects. While other members of the family such as
APOBEC3G are believed to act by editing
ssDNA by removing an amino group from
cytosine in DNA, introducing a cytosine to
uracil change which can ultimately lead to a
cytosine to
thymine mutation, one study suggests that APOBEC3A can inhibit
parvoviruses by another mechanism.[4] The cellular function of APOBEC3A is likely to be the destruction of foreign DNA through extensive deamination of cytosine.Stenglein MD, Burns MB, Li M, Lengyel J, Harris RS (February 2010).
"APOBEC3 proteins mediate the clearance of foreign DNA from human cells". Nature Structural & Molecular Biology. 17 (2): 222–9.
doi:
10.1038/nsmb.1744.
PMC2921484.
PMID20062055.
This gene is a member of the polynucleotide cytosine deaminase gene family. It is one of seven related genes or pseudogenes found in a cluster, thought to result from gene duplication, on chromosome 22. Members of the cluster encode proteins that are structurally and functionally related to the C to U RNA-editing cytidine deaminase APOBEC1. The APOBEC3 family of DNA editing enzymes are thought to be part of the
innate immune system by restricting
retroviruses, mobile genetic elements like
retrotransposons and
endogenous retroviruses. In addition, APOBEC3A is an important restrictive factor for HIV-1 and other retroviruses such as
murine leukemia virus,[5][6]
Structure
The basic structure APOBEC3A consists of a 5 stranded central
β-sheet surrounded by 6
α-helices and a single catalytically active
zinc finger domain. Similar to all APOBEC3 catalytic domains, the domain is a HAEx28Cx2-4C zinc binding motif. In such motifs,
histidine residues (or
cysteine residues in RNA cytidine deaminases) coordinate the
zinc ion while a
glutamic acid stabilizes the transition state and the
proton shuttle. The
zinc ion, in this case, is specifically coordinated by residues H70, C101 and C106.[7][8][9][10]
A3A-ssDNA structure
Single stranded
DNA, abbreviated ssDNA, is the substrate that is catalyzed in the C→U deamination reaction of APOBEC3A.
Activity
A3A has the highest catalytic activity among the APOBEC3 protein family.[11]
mRNA editing activity
A3A was first found to induce an alternative form of the mRNA editing, G>A, in Wilms' Tumor-1 (WT1) mRNA in cord blood mononuclear cells, particularly in the genomic polymorphic sites, apparently reflecting an amination process rather than a de-amination one.[12] This was soon followed by a study showing A3A induce canonical widespread C>U mRNA editing in human monocytes and macrophages.[13]
Effect of pH on APOBEC3A
APOBEC3A functions best at an acidic
pH, with maximal catalytic activity at pH 5.5.[14][15] Another protein of the APOBEC family very similar to A3A, APOBEC3B, showed little activity at pH 4.5 and 4.0 and a similar assumption can be made of A3A activity at these lower pH levels.[15]
A3A affinity for ssDNA is also
pH dependent and closely correlated to the deamination activity of APOBEC3A. The
enzyme has the highest affinity for ssDNA at
pH 5.5 demonstrating that A3A's maximal catalytic activity and highest affinity for ssDNA occur at a similar
pH.[16]
Mechanism of Action
A3A has become an increasingly widely studied A3 because of its high catalytic activity compared to its family members and its relatively unknown mechanisms compared to more popular APOBEC3's such as
APOBEC3G.
Wedekind JE, Dance GS, Sowden MP, Smith HC (April 2003). "Messenger RNA editing in mammals: new members of the APOBEC family seeking roles in the family business". Trends in Genetics. 19 (4): 207–16.
doi:
10.1016/S0168-9525(03)00054-4.
PMID12683974.
Rasmussen HH, van Damme J, Puype M, Gesser B, Celis JE, Vandekerckhove J (December 1992). "Microsequences of 145 proteins recorded in the two-dimensional gel protein database of normal human epidermal keratinocytes". Electrophoresis. 13 (12): 960–9.
doi:
10.1002/elps.11501301199.
PMID1286667.
S2CID41855774.
Jarmuz A, Chester A, Bayliss J, Gisbourne J, Dunham I, Scott J, Navaratnam N (March 2002). "An anthropoid-specific locus of orphan C to U RNA-editing enzymes on chromosome 22". Genomics. 79 (3): 285–96.
doi:
10.1006/geno.2002.6718.
PMID11863358.
Izmailova E, Bertley FM, Huang Q, Makori N, Miller CJ, Young RA, Aldovini A (February 2003). "HIV-1 Tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages". Nature Medicine. 9 (2): 191–7.
doi:
10.1038/nm822.
PMID12539042.
S2CID26145639.