An Extended Structure of the APOBEC3G Catalytic Domain Suggests a Unique Holoenzyme Model

Elena Harjes, Phillip J. Gross, Kuan Ming Chen, Yongjian Lu, Keisuke Shindo, Roni Nowarski, John D. Gross, Moshe Kotler, Reuben Harris, Hiroshi Matsuo

Research output: Contribution to journalArticlepeer-review

92 Scopus citations


Human APOBEC3G (A3G) belongs to a family of polynucleotide cytidine deaminases. This family includes APOBEC1 and AID, which edit APOB mRNA and antibody gene DNA, respectively. A3G deaminates cytidines to uridines in single-strand DNA and inhibits the replication of human immunodeficiency virus-1, other retroviruses, and retrotransposons. Although the mechanism of A3G-catalyzed DNA deamination has been investigated genetically and biochemically, atomic details are just starting to emerge. Here, we compare the DNA cytidine deaminase activities and NMR structures of two A3G catalytic domain constructs. The longer A3G191-384 protein is considerably more active than the shorter A3G198-384 variant. The longer structure has an α1-helix (residues 201-206) that was not apparent in the shorter protein, and it contributes to catalytic activity through interactions with hydrophobic core structures (β1, β3, α5, and α6). Both A3G catalytic domain solution structures have a discontinuous β2 region that is clearly different from the continuous β2 strand of another family member, APOBEC2. In addition, the longer A3G191-384 structure revealed part of the N-terminal pseudo-catalytic domain, including the interdomain linker and some of the last α-helix. These structured residues (residues 191-196) enabled a novel full-length A3G model by providing physical overlap between the N-terminal pseudo-catalytic domain and the new C-terminal catalytic domain structure. Contrary to predictions, this structurally constrained model suggested that the two domains are tethered by structured residues and that the N- and C-terminal β2 regions are too distant from each other to participate in this interaction.

Original languageEnglish (US)
Pages (from-to)819-832
Number of pages14
JournalJournal of Molecular Biology
Issue number5
StatePublished - Jun 26 2009

Bibliographical note

Funding Information:
We thank S. Harjes for assistance with YASARA modeling; J. Albin, M. Stenglein, and K. Walters for feedback; S. Gad for technical assistance; and laboratory members for helpful discussions. The University of Minnesota Supercomputing Institute and NMR Core (NSF BIR-961477) and the University of California San Francisco and University of California Berkeley QB3 NMR Cores provided key instrumentation. This work was performed, in part, at the Krueger Laboratory with the support of N. Glick and L. Glick, and P. Weiss and M. Weiss. This work was supported by grants from the National Institutes of Health (AI073167 to H.M., AI064046 to R.S.H., and GM082250 to the HARC center at the University of California San Francisco and the University of California Berkeley), the Medica Foundation Minnesota Partnership for Biotechnology and Medical Genomics (to H.M. and R.S.H.), and the United States–Israel Binational Science Foundation (to M.K.).


  • DNA deamination
  • DNA editing
  • NMR structure
  • retrovirus restriction


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