May 2010

[JBC] Viral Inactivation at Work

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Model showing how an APOBEC3G monomer’s CD2 domain (wheat) causes deoxycytodine deamination of 5’ located cytodines (red).

Successful replication of viruses requires that they overcome a number of hurdles inside host cells. APOBEC3G (Apo3G) is a human protein that interferes with the replication of HIV-1 by mutating viral cDNA by deoxycytodine deamination. While the antiviral effects of Apo3G make it important to understand the mechanism of this protein, structural and biochemical analyses have been impeded by the oligomeric state of highly purified Apo3G. Here, the authors used structure-guided predictions to identify two amino acids at the non-catalytic CD1-interaction domain of Apo3G. When mutated at these sites, Apo3G was primarily purified as a monomer, demonstrating that the CD1-interaction domain is crucial to the dimerization of Apo3G. Monomeric Apo3G efficiently bound several nucleic acid sequences and exhibited 3 --> 5’ deamination polarity and processivity, suggesting that the monomer is biochemically similar to the native protein. Simultaneously, Apo3G’s CD1 domain appeared to be essential for the catalytic activity of Apo3G’s CD2 domain, suggesting that CD1 enhances CD2-mediated catalysis. Together, these results provide a structure-based model to explain the catalytic behavior of Apo3G, informing the mechanism of its antiviral activity.

A Structural Model for Deoxycytidine Deamination Mechanisms of the HIV-1 Inactivation Enzyme APOBEC3G

Linda Chelico, Courtney Prochnow, Dorothy A. Erie, Xiaojiang S. Chen and Myron F. Goodman

J. Biol. Chem., published online March 8, 2010

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