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APOBEC3A

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APOBEC3A
Available structures
PDBHuman UniProt search: PDBe RCSB
Identifiers
AliasesAPOBEC3A, A3A, ARP3, PHRBN, bK150C2.1, apolipoprotein B mRNA editing enzyme catalytic subunit 3A
External IDsOMIM: 607109; HomoloGene: 82288; GeneCards: APOBEC3A; OMA:APOBEC3A - orthologs
Orthologs
SpeciesHumanMouse
Entrez

200315

n/a

Ensembl

ENSG00000128383
ENSG00000262156

n/a

UniProt

P31941

n/a

RefSeq (mRNA)

NM_145699
NM_001270406

n/a

RefSeq (protein)

NP_001257335
NP_663745

n/a

Location (UCSC)Chr 22: 38.95 – 38.99 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

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 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.[4] The cellular function of APOBEC3A is likely to be the destruction of foreign DNA through extensive deamination of cytosine.[5]

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 lentiviruses found in primates.[6] APOBEC3A is highly expressed in monocytes and macrophages upon stimulation with interferon.[7]

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 and cytosine residues coordinate the zinc ion while a glutamic acid stabilizes the transition state and the proton shuttle. The zinc ion is specifically coordinated by residues H70, C101 and C106.[8][9][10][11]

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.[12]

Effect of pH on APOBEC3A

APOBEC3A functions best at an acidic pH, with maximal catalytic activity at pH 5.5.[6][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. ^ a b c ENSG00000262156 GRCh38: Ensembl release 89: ENSG00000128383, ENSG00000262156 – Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ "Entrez Gene: APOBEC3A apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3A".
  4. ^ Narvaiza I, Linfesty DC, Greener BN, Hakata Y, Pintel DJ, Logue E, et al. (May 2009). Jung JU (ed.). "Deaminase-independent inhibition of parvoviruses by the APOBEC3A cytidine deaminase". PLOS Pathogens. 5 (5): e1000439. doi:10.1371/journal.ppat.1000439. PMC 2678267. PMID 19461882.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ Mark D. Stenglein; Michael B. Burns; Michael B. Burns; Joy Lengyel; Reuben S. Harris (2010). "APOBEC3 proteins mediate the clearance of foreign DNA from human cells". Nature Structural & Molecular Biology. 17 (2): 222–229. doi:10.1038/nsmb.1744. PMC 2921484. PMID 20062055
  6. ^ a b Pham P, Landolph A, Mendez C, Li N, Goodman MF (October 2013). "A biochemical analysis linking APOBEC3A to disparate HIV-1 restriction and skin cancer". The Journal of Biological Chemistry. 288 (41): 29294–304. doi:10.1074/jbc.M113.504175. PMC 3795231. PMID 23979356.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  7. ^ 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. PMC 2921484. PMID 20062055.
  8. ^ Kouno, Takahide; Silvas, Tania V.; Hilbert, Brendan J.; Shandilya, Shivender M. D.; Bohn, Markus F.; Kelch, Brian A.; Royer, William E.; Somasundaran, Mohan; Kurt Yilmaz, Nese; Matsuo, Hiroshi; Schiffer, Celia A. (April 2017). "Crystal structure of APOBEC3A bound to single-stranded DNA reveals structural basis for cytidine deamination and specificity". Nature Communications. 8 (1): 15024. doi:10.1038/ncomms15024. ISSN 2041-1723. PMC 5414352. PMID 28452355.
  9. ^ Byeon, In-Ja L.; Ahn, Jinwoo; Mitra, Mithun; Byeon, Chang-Hyeock; Hercík, Kamil; Hritz, Jozef; Charlton, Lisa M.; Levin, Judith G.; Gronenborn, Angela M. (2013). "NMR structure of human restriction factor APOBEC3A reveals substrate binding and enzyme specificity". Nature Communications. 4: 1890. doi:10.1038/ncomms2883. ISSN 2041-1723. PMC 3674325. PMID 23695684.
  10. ^ McDaniel, Yumeng Z; Wang, Dake; Love, Robin P; Adolph, Madison B; Mohammadzadeh, Nazanin; Chelico, Linda; Mansky, Louis M (2020-01-16). "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. doi:10.1093/nar/gkz1164. ISSN 0305-1048. PMC 7026630. PMID 31943071.
  11. ^ Bohn, Markus-Frederik; Shandilya, Shivender M.D.; Silvas, Tania V.; Nalivaika, Ellen A.; Kouno, Takahide; Kelch, Brian A.; Ryder, Sean P.; Kurt-Yilmaz, Nese; Somasundaran, Mohan; Schiffer, Celia A. (2015-05-05). "The ssDNA Mutator APOBEC3A is Regulated by Cooperative Dimerization". Structure. 23 (5): 903–911. doi:10.1016/j.str.2015.03.016. ISSN 0969-2126. PMC 4874493. PMID 25914058.
  12. ^ Carpenter MA, Li M, Rathore A, Lackey L, Law EK, Land AM, et al. (October 2012). "Methylcytosine and normal cytosine deamination by the foreign DNA restriction enzyme APOBEC3A". The Journal of Biological Chemistry. 287 (41): 34801–8. doi:10.1074/jbc.m112.385161. PMC 3464582. PMID 22896697.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  13. ^ a b Ito F, Fu Y, Kao SA, Yang H, Chen XS (June 2017). "Family-Wide Comparative Analysis of Cytidine and Methylcytidine Deamination by Eleven Human APOBEC Proteins". Journal of Molecular Biology. 429 (12): 1787–1799. doi:10.1016/j.jmb.2017.04.021. PMC 5530319. PMID 28479091.
  14. ^ a b Silvas, Tania V.; Hou, Shurong; Myint, Wazo; Nalivaika, Ellen; Somasundaran, Mohan; Kelch, Brian A.; Matsuo, Hiroshi; Kurt Yilmaz, Nese; Schiffer, Celia A. (December 2018). "Substrate sequence selectivity of APOBEC3A implicates intra-DNA interactions". Scientific Reports. 8 (1): 7511. doi:10.1038/s41598-018-25881-z. ISSN 2045-2322. PMC 5951847. PMID 29760455.

Further reading

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