title: Phosphorylation directly regulates the intrinsic DNA cytidine deaminase activity of activation-induced deaminase and APOBEC3G protein.
abstract: The beneficial effects of DNA cytidine deamination by activation-induced deaminase (AID; antibody gene diversification) and APOBEC3G (retrovirus restriction) are tempered by probable contributions to carcinogenesis. Multiple regulatory mechanisms serve to minimize this detrimental outcome. Here, we show that phosphorylation of a conserved threonine attenuates the intrinsic activity of activation-induced deaminase (Thr-27) and APOBEC3G (Thr-218). Phospho-null alanine mutants maintain intrinsic DNA deaminase activity, whereas phospho-mimetic glutamate mutants are inactive. The phospho-mimetic variants fail to mediate isotype switching in activated mouse splenic B lymphocytes or suppress HIV-1 replication in human T cells. Our data combine to suggest a model in which this critical threonine acts as a phospho-switch that fine-tunes the adaptive and innate immune responses and helps protect mammalian genomic DNA from procarcinogenic lesions.
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, Institute for Molecular Virology, and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Zachary L
authors.initials: ZL
authors.lastname: Demorest
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
mesh_terms: D000071480:APOBEC-3G Deaminase; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology*; D002460:Cell Line; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D051379:Mice; D008954:Models, Biological; D020125:Mutation, Missense; D010766:Phosphorylation / Q000235:genetics; D013601:T-Lymphocytes / Q000201:enzymology*; D014779:Virus Replication / Q000502:physiology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; C496166:APOBEC3G protein, mouse; D003564:Cytidine Deaminase