Article: article from journal or magazin.
Structure-function analyses point to a polynucleotide-accommodating groove essential for APOBEC3A restriction activities.
Journal of Virology
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Members of the human APOBEC3 family of editing enzymes can inhibit various mobile genetic elements. APOBEC3A (A3A) can block the retrotransposon LINE-1 and the parvovirus adeno-associated virus type 2 (AAV-2) but does not inhibit retroviruses. In contrast, APOBEC3G (A3G) can block retroviruses but has only limited effects on AAV-2 or LINE-1. What dictates this differential target specificity remains largely undefined. Here, we modeled the structure of A3A based on its homology with the C-terminal domain of A3G and further compared the sequence of human A3A to those of 11 nonhuman primate orthologues. We then used these data to perform a mutational analysis of A3A, examining its ability to restrict LINE-1, AAV-2, and foreign plasmid DNA and to edit a single-stranded DNA substrate. The results revealed an essential functional role for the predicted single-stranded DNA-docking groove located around the A3A catalytic site. Within this region, amino acid differences between A3A and A3G are predicted to affect the shape of the polynucleotide-binding groove. Correspondingly, transferring some of these A3A residues to A3G endows the latter protein with the ability to block LINE-1 and AAV-2. These results suggest that the target specificity of APOBEC3 family members is partly defined by structural features influencing their interaction with polynucleotide substrates.
Animals, Base Sequence, Cytidine Deaminase/chemistry, Cytidine Deaminase/genetics, DNA, Single-Stranded/genetics, DNA, Single-Stranded/metabolism, Dependovirus/genetics, Dependovirus/metabolism, HEK293 Cells, Haplorhini, Hela Cells, Humans, Long Interspersed Nucleotide Elements/genetics, Long Interspersed Nucleotide Elements/physiology, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Plasmids, Polynucleotides/chemistry, Polynucleotides/metabolism, Proteins/chemistry, Proteins/genetics, Retroelements/genetics, Sequence Alignment, Sequence Analysis, DNA, Sequence Homology, Amino Acid, Structure-Activity Relationship, Substrate Specificity
Web of science
Last modification date