DNA deamination in immunity: AID in the context of its APOBEC relatives

The activation-induced cytidine deaminase (AID)/apolipoprotein B RNA-editing catalytic component (APOBEC) family is a vertebrate-restricted subgrouping of a superfamily of zinc (Zn)-dependent deaminases that has members distributed throughout the biological world. AID and APOBEC2 are the oldest family members with APOBEC1 and the APOBEC3s being later arrivals restricted to placental mammals. Many AID/APOBEC family members exhibit cytidine deaminase activity on polynucleotides, although in different physiological contexts. Here, we examine the AID/APOBEC proteins in the context of the entire Zn-dependent deaminase superfamily. On the basis of secondary structure predictions, we propose that the cytosine and tRNA deaminases are likely to provide better structural paradigms for the AID/APOBEC family than do the cytidine deaminases, to which they have conventionally been compared. These comparisons yield predictions concerning likely polynucleotide-interacting residues in AID/APOBEC3s, predictions that are supported by mutagenesis studies. We also focus on a specific comparison between AID and the APOBEC3s. Both are DNA deaminases that function in immunity and are responsible for the hypermutation of their target substrates. AID functions in the adaptive immune system to diversify antibodies with targeted DNA deamination being central to this function. APOBEC3s function as part of an innate pathway of immunity to retroviruses with targeted DNA deamination being central to their activity in retroviral hypermutation. However, the mechanism by which the APOBEC3s fulfill their function of retroviral restriction remains unresolved.