title: Structural phylogenetic analysis of activation-induced deaminase function.
abstract: 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.
authors.affiliation: Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: H Travis
authors.initials: HT
authors.lastname: Ichikawa
authors.forename: Mark P
authors.initials: MP
authors.lastname: Sowden
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Torelli
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bachl
authors.forename: Pinwei
authors.initials: P
authors.lastname: Huang
authors.forename: Geoffrey S C
authors.initials: GS
authors.lastname: Dance
authors.forename: Shauna H
authors.initials: SH
authors.lastname: Marr
authors.forename: Jacques
authors.initials: J
authors.lastname: Robert
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Wedekind
authors.forename: Harold C
authors.initials: HC
authors.lastname: Smith
authors.forename: Andrea
authors.initials: A
authors.lastname: Bottaro
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain / Q000235:genetics; D002460:Cell Line; D003001:Cloning, Molecular; D003564:Cytidine Deaminase / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D041681:NIH 3T3 Cells; D049790:Nuclear Export Signals / Q000235:genetics; D010802:Phylogeny; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D023741:Takifugu; D029867:Xenopus Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D014982:Xenopus laevis; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D049790:Nuclear Export Signals; D011993:Recombinant Fusion Proteins; D029867:Xenopus Proteins; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase