Structural phylogenetic analysis of activation-induced deaminase function.
In mammals, activation-induced deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) of Ig genes. SHM and CSR activities require separate regions within AID. A chromosome region maintenance 1 (CRM1)-dependent nuclear export signal (NES) at the AID C terminus is necessary for CSR, and has been suggested to associate with CSR-specific cofactors. CSR appeared late in AID evolution, during the emergence of land vertebrates from bony fish, which only display SHM. Here, we show that AID from African clawed frog (Xenopus laevis), but not pufferfish (Takifugu rubripes), can induce CSR in AID-deficient mouse B cells, although both are catalytically active in bacteria and mammalian cell systems, albeit at decreased level. Like mammalian AID, Takifugu AID is actively exported from the cell nucleus by CRM1, and the Takifugu NES can substitute for the equivalent region in human AID, indicating that all the CSR-essential NES motif functions evolutionarily predated CSR activity. We also show that fusion of the Takifugu AID catalytic domain to the entire human noncatalytic domain restores activity in mammalian cells, suggesting that AID features mapping within the noncatalytic domain, but outside the NES, influence its function.
PubMed ID: 16785531
Article link: J Immunol.
Grant support: AI 059830 NIAID NIH HHS , AI 45012 NIAID NIH HHS , AI 54369 Z NIAID NIH HHS , CA 107355 NCI NIH HHS , CA 107355 NCI NIH HHS , CA 107355 NCI NIH HHS , CA 107355 NCI NIH HHS , CA 107355 NCI NIH HHS , CA 107355 NCI NIH HHS , DK 43739 NIDDK NIH HHS , GM 63162 NIGMS NIH HHS , R25 GM 64133 NIGMS NIH HHS , RR 15934 NCRR NIH HHS , T32 HL 07152 NHLBI NIH HHS , T32 HL 07152 NHLBI NIH HHS , T32 HL 07152 NHLBI NIH HHS , T32 HL 07152 NHLBI NIH HHS , T32 HL 07152 NHLBI NIH HHS , T32 HL 07152 NHLBI NIH HHS
Genes referenced: aicda xpo1