Activation-induced cytidine deaminase splice variants are defective because of the lack of structural support for the catalytic site.
Recently, conflicting results were reported on the hypermutation activity of activation-induced cytidine deaminase (AID) splice variants. With the generation of single point mutations, we studied the structure-function relationship of the amino acids that are commonly absent from all described splice variants. The results from this analysis pointed to several amino acids that are required for class switch recombination (CSR), without perturbing cellular localization or nucleocytoplasmic shuttling. A defect in deaminase activity was found to underlie this CSR deficiency. Interestingly, the most debilitating mutations concentrated on hydrophobic amino acids, suggesting a structural role for this part of the protein. Indeed, by generating homologous amino acid replacements, CSR activity could be restored. These results are in agreement with recent reports on the protein structure of the AID homolog APOBEC3G, suggesting a similar protein composition. In addition, the findings underscore that AID splice variants are unlikely to have preservation of catalytic activity.
van Maldegem
Febe
F
Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Jibodh
R Aarti
RA
van Dijk
Remco
R
Bende
Richard J
RJ
van Noesel
Carel J M
CJ
D017398:Alternative Splicing; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D020134:Catalytic Domain / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D020125:Mutation, Missense; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase