The AID/APOBEC family of nucleic acid mutators - PubMed (original) (raw)
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The AID/APOBEC family of nucleic acid mutators
Silvestro G Conticello. Genome Biol. 2008.
Abstract
The AID/APOBECs, a group of cytidine deaminases, represent a somewhat unusual protein family that can insert mutations in DNA and RNA as a result of their ability to deaminate cytidine to uridine. The ancestral AID/APOBECs originated from a branch of the zinc-dependent deaminase superfamily at the beginning of the vertebrate radiation. Other members of the family have arisen in mammals and present a history of complex gene duplications and positive selection. All AID/APOBECs have a characteristic zinc-coordination motif, which forms the core of the catalytic site. The crystal structure of human APOBEC2 shows remarkable similarities to that of the bacterial tRNA-editing enzyme TadA, which suggests a conserved mechanism by which polynucleotides are recognized and deaminated. The AID/APOBECs seem to have diverse roles. AID and the APOBEC3s are DNA mutators, acting in antigen-driven antibody diversification processes and in an innate defense system against retroviruses, respectively. APOBEC1 edits the mRNA for apolipoprotein B, a protein involved in lipid transport. A detailed understanding of the biological roles of the family is still some way off, however, and the functions of some members of the family are completely unknown. Given their ability to mutate DNA, a role for the AID/APOBECs in the onset of cancer has been proposed.
Figures
Figure 1
Schematic representation of the evolutionary relationships between the AID/APOBECs and the rest of the zinc-dependent deaminases. The only other zinc-dependent deaminase families widely expressed in metazoans and from which the AID/APOBECs (shaded in red) could have originated are the cytidine deaminases (CDA), the dCMP deaminases (DCDT) or the tRNA adenosine deaminases (Tad/ADAT2) (all shown in orange). CDAs and DCDTs act on free pyrimidines in the salvage pathway, the Tad/ADAT2s edit adenosine 34 at the anticodon of various tRNAs to inosine and are essential in bacteria, yeast and metazoans [6]. AID/APOBECs are unlikely to have originated from CDAs because of the differences in gene organization and catalytic domain [7,10]; DCDTs, despite the similar secondary structure, differ substantially from the AID/APOBECs in their substrate (free nucleotides), dependency on Mg and dCTP, and aggregation into homohexamers [108]. Phylogenetic data [10], species representation, and structural/functional features favor the tRNA-editing enzymes as the origin of the AID/APOBECs [7,8], a model supported by the observation that ADAT2 from trypanosomes can deaminate DNA [9]. The tRNAAla adenosine 37 deaminases type 1 (ADAT1) and the mRNA adenosine deaminases 1, 2, and 3 (ADARs) (shaded in green) are thought to have originated from the Tad/ADAT2 family independently of the AID/APOBECs. CoDA, cytosine deaminases; RibD, riboflavin deaminases; GuanineD, guanine deaminases.
Figure 2
Phylogenetic relationships within the AID/APOBEC gene family. The neighbor-joining tree shown here is generated from a protein alignment of the exon encoding the zinc-coordinating motif (the alignment is provided as Additional data file 1). The position of the agnathan (sea lamprey) AID (indicated by the arrow), separated from the clade comprising all the other AID/APOBECs, could suggest that all family members have originated from the ancestral AID. The different clusters in the AID/APOBEC family are identified, with the APOBEC3 cluster further divided into Z1a, Z1b, and Z2 clades (for the nomenclature of the APOBEC3 subgroups see [10]). Each domain of the double-domained APOBEC3s is included individually, with the amino-terminal and carboxy-terminal domains labeled [N] and [C], respectively. While APOBEC1 has been described only in mammals, the APOBEC2 group is found in all jawed vertebrates, including the primitive ghost shark. The duplication of the APOBEC2 locus after an ancient genome duplication in bony fish has been maintained, resulting in two coevolving APOBEC2 genes. The organisms in which each group is found are indicated below the clade label. Clades are collapsed for clarity, and only nodes with a bootstrap value greater than 50 are shown. The sequences used are either described in [10,12] or obtained from the Ensembl Genome Browser [109]. The sequences for the ghost shark were obtained using the AID/APOBECs as queries in BLAST searches on the Callorhinchus milii genome shotgun contigs (GenBank accession numbers: AID, AAVX01329030; APOBEC2, AAVX01039499; APOBEC4, AAVX01642881).
Figure 3
Logo alignment of the exon encoding the zinc-coordinating motif in the AID, APOBEC1, APOBEC3, and APOBEC2 clusters. The height of the letter represents the conservation of that given residue. The zinc-coordinating H [AV]E-x(24-36)-PCxxC motif is labeled. The secondary structure, predicted from the APOBEC2 structure, is shown below the alignment. The α helices are shown as cylinders and the β-strands as arrows. α Helices 2 and 3, providing the scaffold for the catalytic core, are labeled in blue. The conserved loops that might have a role in substrate recognition are color-coded (pink and orange) and indicated by arrows. The Logo alignment was generated using WebLogo [110] on a subset of the alignment provided as Additional data file 1 in which APOBEC4 and outgroup sequences were excluded.
Figure 4
Three-dimensional structure of APOBEC2 [20]. α Helices 2 and 3, which hold the histidine and the cysteines forming the catalytic pocket, are indicated in blue. The zinc atom is indicated as a yellow sphere, the residues coordinating the zinc atom are colored in red, and the glutamate acting as proton donor in purple (beneath the zinc atom). The β strands providing the molecule's scaffold are indicated in bright green. The loops that might play a role in substrate recognition are indicated: the loop conserved in TadA [21] is in orange and the SSS loop is in pink. PDB: 2NYT.
References
- Navaratnam N, Morrison JR, Bhattacharya S, Patel D, Funahashi T, Giannoni F, Teng BB, Davidson NO, Scott J. The p27 catalytic subunit of the apolipoprotein B mRNA editing enzyme is a cytidine deaminase. J Biol Chem. 1993;268:20709–20712. - PubMed
- Muramatsu M, Sankaranand VS, Anant S, Sugai M, Kinoshita K, Davidson NO, Honjo T. Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. J Biol Chem. 1999;274:18470–18476. doi: 10.1074/jbc.274.26.18470. - DOI - PubMed
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