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J. Biol. Chem., Vol. 281, Issue 50, 38122-38126, December 15, 2006

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Nanostructures of APOBEC3G Support a Hierarchical Assembly Model of High Molecular Mass Ribonucleoprotein Particles from Dimeric Subunits^*

Joseph E. Wedekind¹, Richard Gillilan, Alena Janda², Jolanta Krucinska², Jason D. Salter, Ryan P. Bennett³, Jay Raina^¶, and Harold C. Smith⁴

From the Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, the Macromolecular Structure Facility at the Cornell High-Energy Synchrotron Source (MacCHESS), Cornell University, Ithaca, New York 14853, and ^¶Immunodiagnostics Inc., Woburn, Massachusetts 01801

Human APOBEC3G (hA3G) is a cytidine deaminase that restricts human immunodeficiency virus (HIV)-1 infection in a vif (the virion infectivity factor from HIV)-dependent manner. hA3G from HIV-permissive activated CD4+ T-cells exists as an inactive, high molecular mass (HMM) complex that can be transformed in vitro into an active, low molecular mass (LMM) variant comparable with that of HIV-non-permissive CD4+ T-cells. Here we present low resolution structures of hA3G in HMM and LMM forms determined by small angle x-ray scattering and advanced shape reconstruction methods. The results show that LMM particles have an extended shape, dissimilar to known cytidine deaminases, featuring novel tail-to-tail dimerization. Shape analysis of LMM and HMM structures revealed how symmetric association of dimers could lead to minimal HMM variants. These observations imply that the disruption of cellular HMM particles may require regulation of protein-RNA, as well as protein-protein interactions, which has implications for therapeutic development.

Received for publication, September 19, 2006 , and in revised form, October 23, 2006.

^* This work was supported by Grant AI058789 from NIAID/National Institutes of Health. CHESS was supported by National Science Foundation Grant DMR 0225180, and the MacCHESS facility was supported by National Institutes of Health Grant RR-01646. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Methods, Refs. 1–6, Figs. S1–S4, and Table S1.

² These authors contributed equally to this work.

³ Supported by National Institutes of Health Grant T32 AI49815.

¹ To whom correspondence may be addressed: Dept. of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Box 712, Rochester, NY 14642. Tel.: 585-273-4516; Fax: 585-271-2683; E-mail: joseph_wedekind{at}urmc.rochester.edu. ⁴ To whom correspondence may be addressed: Dept. of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Box 712, Rochester, NY 14642. Tel.: 585-275-4267; Fax: 585-271-2683; E-mail: harold.smith{at}rochester.edu.

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