Cytidine deaminase efficiency of the lentiviral viral restriction factor APOBEC3C correlates with dimerization.
The seven APOBEC3 (A3) enzymes in primates restrict HIV/SIV replication to differing degrees by deaminating cytosine in viral (-)DNA, which forms promutagenic uracils that inactivate the virus. A polymorphism in human APOBEC3C (A3C) that encodes an S188I mutation increases the enzymatic activity of the protein and its ability to restrict HIV-1, and correlates with increased propensity to form dimers. However, other hominid A3C proteins only have an S188, suggesting they should be less active like the common form of human A3C. Nonetheless, here we demonstrate that chimpanzee and gorilla A3C have approximately equivalent activity to human A3C I188 and that chimpanzee and gorilla A3C form dimers at the same interface as human A3C S188I, but through different amino acids. For each of these hominid A3C enzymes, dimerization enables processivity on single-stranded DNA and results in higher levels of mutagenesis during reverse transcription in vitro and in cells. For increased mutagenic activity, formation of a dimer was more important than specific amino acids and the dimer interface is unique from other A3 enzymes. We propose that dimerization is a predictor of A3C enzyme activity.
Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Madison B
MB
Adolph
Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Anjuman
A
Ara
Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Yuqing
Y
Feng
Department of Microbiology, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Cristina J
CJ
Wittkopp
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Michael
M
Emerman
Department of Bioengineering and Therapeutic Science and California Institute for Quantitative Biology, University of California, San Francisco, San Francisco, CA, USA.
James S
JS
Fraser
Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Linda
L
Chelico
D000818:Animals; D003564:Cytidine Deaminase / Q000737:chemistry* / Q000378:metabolism*; D004277:DNA, Single-Stranded / Q000378:metabolism; D006071:Gorilla gorilla; D006801:Humans; D016296:Mutagenesis; D002679:Pan troglodytes; D055503:Protein Multimerization; D017433:Protein Structure, Secondary
D004277:DNA, Single-Stranded; C495795:APOBEC3C protein, human; D003564:Cytidine Deaminase