Abstract of the PDB Structure's related Publication:
Activation-induced deoxycytidine deaminase (AID) initiates somatic hypermutation (SHM) and class-switch recombination (CSR) by deaminating C→U during transcription of Ig-variable (V) and Ig-switch (S) region DNA, which is essential to produce high-affinity antibodies. Here we report the crystal structure of a soluble human AID variant at 2.8Å resolution that favors targeting WRC motifs (W=A/T, R=A/G) in vitro, and executes Ig V SHM in Ramos B-cells. A specificity loop extending away from the active site to accommodate two purine bases next to C, differs significantly in sequence, length, and conformation from APOBEC proteins Apo3A and Apo3G, which strongly favor pyrimidines at -1 and -2 positions. Individual amino acid contributions to specificity and processivity were measured in relation to a proposed ssDNA binding cleft. This study provides a structural basis for residue contributions to DNA scanning properties unique to AID, and for disease mutations in human HIGM-2 syndrome.
Activation Induced cytidine Deaminase belongs to the mammalian enzyme family known as the "activation-induced deaminase/apolipoprotein B-mRNA-editing enzyme catalytic polypeptide like" (AID/APOBEC) protein family. AID/APOBEC share three major common elements, ultimately displaying a conserved protein architecture (Pecori et al. 2022 ).
They comprise the catalytic domain that contains an enzymatic pocket that partially overlpas with the substrate binding surface (Pecori et al. 2022 ).
Some of these enzymes have a cofactor interacting region and certain sequene elements that define their subcellular localization (Pecori et al. 2022 ).AID can both deaminate RNA and ssDNA, as well. However, no RNA modification has been observed so far. AID expression (Pecori et al. 2022 ). AID expression is regulated both transcriptionally and post-transcriptionally.
MicroRNAs (miR-155, miR-181b, miR-361, and miR-93) have a major role in AID suppression, targeting 3'-UTR (Takai et al. 2015).
AID preferentially deaminates DNA cytidine in the 5'-WRC-3' sequence context (W=dA/dT, R=dC/dG). AID catalyzes deamination within variable antibody region V(D)J gene segments of Immunoglobuline (Ig) genes in B cells, leading to somatic hypermutations (SHM). It also targets repetitive 'switch' regions leading to class switch recombination (Takai et al. 2015).
Post-translational modifications are essential for AID activity to be performed. Phosphorylation is indeed important for modulating AID's activity in B cells, where AID is phosphorylated on serine 38 (Ser38) (Takai et al. 2015).