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J. Biol. Chem., Vol. 281, Issue 48, 36624-36631, December 1, 2006

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Reversed Functional Organization of Mouse and Human APOBEC3 Cytidine Deaminase Domains^*

From the Infectious Disease Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037

APOBEC3 proteins comprise a multigene family of antiviral cytidine deaminases that are active against human immunodeficiency virus, simian immunodeficiency virus, endogenous retroelements. The Vif protein of lentiviruses binds to specific APOBEC3 proteins, notably A3F and A3G, to induce their degradation by proteasomes. APOBEC3 proteins are of two types, those with a single deaminase domain such as human (h)A3A and hA3C and those with two cytidine deaminase domains (CDD) such as hA3G, hA3F, hA3B and the mouse APOBEC3, mA3. In hA3G, both active sites are required for antiviral function but serve separate functions. CDD2 mediates the C to U deamination of the human immunodeficiency virus type 1 genome, whereas CDD1 binds the viral RNA to allow for virion packaging. Here we analyzed the role of the two domains in additional APOBEC3 family members. We analyzed APOBEC3 proteins in which either the critical glutamic acid residue or the Zn²⁺ coordination amino acid residues in the active sites were mutated. The separation of function of the domains is maintained in hA3B and hA3F, but in the mouse protein mA3, the roles of the two domains are reversed. Deamination is mediated by CDD1, whereas encapsidation and dimerization are mediated by CDD2. Antiviral function of each of the APOBEC3 proteins was largely attributable to deaminase activity. Deaminase-independent antiviral activity of the active site mutants was minor. These findings suggest that the two active sites have different functions but that these functions can be interchanged in different APOBEC3 family members.

Received for publication, May 24, 2006 , and in revised form, September 13, 2006.

^* This work was supported in part by National Institutes of Health Grants AI51686, DA14494, and AI58864 and the American Foundation for AIDS Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a Uehara memorial foundation post-doctoral fellowship.

² Elizabeth Glaser Fellow of the Pediatric AIDS Foundation. To whom correspondence should be addressed: Infectious Disease Laboratory, The Salk Institute, 10010 North Torrey Pines Rd., La Jolla, CA 92037-1099. Tel.: 858-453-4100; Fax: 858-554-0341; E-mail: Landau{at}salk.edu.

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