Biology:APOBEC3A

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1] It is a single-domain DNA cytidine 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.[2] The cellular function of APOBEC3A is likely to be the destruction of foreign DNA through extensive deamination of cytosine."APOBEC3 proteins mediate the clearance of foreign DNA from human cells". Nature Structural & Molecular Biology 17 (2): 222–9. February 2010. doi:10.1038/nsmb.1744. PMID 20062055. 

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,[3][4]

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.[5][6][7][8]

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.[9]

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.[10] This was soon followed by a study showing A3A induce canonical widespread C>U mRNA editing in human monocytes and macrophages.[11]

Effect of pH on APOBEC3A

APOBEC3A functions best at an acidic pH, with maximal catalytic activity at pH 5.5.[12][13] 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.[13]

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.[14]

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.

Context dependent binding to ssDNA

The binding of APOBEC3A to its substrate ssDNA is highly dependent on its surrounding nucleotides. The specificity for binding to its target deoxycytidine increases more than ten-fold when the target deoxycytidine is surrounded by deoxythymidine nucleotides.[14]

References

  1. ↑ "Entrez Gene: APOBEC3A apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=200315. 
  2. ↑ "Deaminase-independent inhibition of parvoviruses by the APOBEC3A cytidine deaminase". PLOS Pathogens 5 (5): e1000439. May 2009. doi:10.1371/journal.ppat.1000439. PMID 19461882. 
  3. ↑ "Foamy Viruses, Bet, and APOBEC3 Restriction". Viruses 13 (3): 504. March 2021. doi:10.3390/v13030504. PMID 33803830. 
  4. ↑ "Degradation-Independent Inhibition of APOBEC3G by the HIV-1 Vif Protein". Viruses 13 (4): 617. April 2021. doi:10.3390/v13040617. PMID 33916704. 
  5. ↑ "Crystal structure of APOBEC3A bound to single-stranded DNA reveals structural basis for cytidine deamination and specificity". Nature Communications 8 (1): 15024. April 2017. doi:10.1038/ncomms15024. PMID 28452355. Bibcode: 2017NatCo...815024K. 
  6. ↑ "NMR structure of human restriction factor APOBEC3A reveals substrate binding and enzyme specificity". Nature Communications 4: 1890. 2013. doi:10.1038/ncomms2883. PMID 23695684. Bibcode: 2013NatCo...4.1890B. 
  7. ↑ "Deamination hotspots among APOBEC3 family members are defined by both target site sequence context and ssDNA secondary structure". Nucleic Acids Research 48 (3): 1353–1371. February 2020. doi:10.1093/nar/gkz1164. PMID 31943071. 
  8. ↑ "The ssDNA Mutator APOBEC3A Is Regulated by Cooperative Dimerization". Structure 23 (5): 903–911. May 2015. doi:10.1016/j.str.2015.03.016. PMID 25914058. 
  9. ↑ "Methylcytosine and normal cytosine deamination by the foreign DNA restriction enzyme APOBEC3A". The Journal of Biological Chemistry 287 (41): 34801–8. October 2012. doi:10.1074/jbc.m112.385161. PMID 22896697. 
  10. ↑ "APOBEC3A is implicated in a novel class of G-to-A mRNA editing in WT1 transcripts". PLOS ONE 10 (3): e0120089. 2015-03-25. doi:10.1371/journal.pone.0120089. PMID 25807502. Bibcode: 2015PLoSO..1020089N. 
  11. ↑ "APOBEC3A cytidine deaminase induces RNA editing in monocytes and macrophages". Nature Communications 6 (1): 6881. April 2015. doi:10.1038/ncomms7881. PMID 25898173. Bibcode: 2015NatCo...6.6881S. 
  12. ↑ "A biochemical analysis linking APOBEC3A to disparate HIV-1 restriction and skin cancer". The Journal of Biological Chemistry 288 (41): 29294–304. October 2013. doi:10.1074/jbc.M113.504175. PMID 23979356. 
  13. ↑ 13.0 13.1 "Family-Wide Comparative Analysis of Cytidine and Methylcytidine Deamination by Eleven Human APOBEC Proteins". Journal of Molecular Biology 429 (12): 1787–1799. June 2017. doi:10.1016/j.jmb.2017.04.021. PMID 28479091. 
  14. ↑ 14.0 14.1 "Substrate sequence selectivity of APOBEC3A implicates intra-DNA interactions". Scientific Reports 8 (1): 7511. May 2018. doi:10.1038/s41598-018-25881-z. PMID 29760455. Bibcode: 2018NatSR...8.7511S. 

Further reading



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