The stability of AID and its function in class-switching are critically sensitive to the identity of its nuclear-export sequence.
The carboxyterminal region of activation-induced deaminase (AID) is required for its function in Ig class switch recombination (CSR) and also contains a nuclear-export sequence (NES). Here, based on an extensive fine-structure mutation analysis of the AID NES, as well as from AID chimeras bearing heterologous NESs, we show that while a functional NES is indeed essential for CSR, it is not sufficient. The precise nature of the NES is critical both for AID stabilization and CSR function: minor changes in the NES can perturb stabilization and CSR without jeopardizing nuclear export. The results indicate that the AID NES fulfills a function beyond simply providing a signal for nuclear export and suggest the possibility that the quality of exportin-binding may be critical to the stabilization of AID and its activity in CSR.
Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, United Kingdom.
Roland
R
Geisberger
Cristina
C
Rada
Michael S
MS
Neuberger
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002645:Chickens; D003564:Cytidine Deaminase / Q000737:chemistry* / Q000378:metabolism*; D004795:Enzyme Stability; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D050505:Mutant Proteins / Q000378:metabolism; D049790:Nuclear Export Signals; D017354:Point Mutation / Q000235:genetics; D021381:Protein Transport; D013329:Structure-Activity Relationship; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D000596:Amino Acids; D050505:Mutant Proteins; D049790:Nuclear Export Signals; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase