Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 46, Pages 19539-19544Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0906652106
Keywords
structure model; deaminase; antiviral
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Funding
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- National Institutes of Health [GM082251]
- National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development
- Ministry of Health, Labor, and Welfare, Japan
- Grants-in-Aid for Scientific Research [21590525] Funding Source: KAKEN
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During coevolution with the host, HIV-1 developed the ability to hijack the cellular ubiquitin/proteasome degradation pathway to counteract the antiviral activity of APOBEC3G (A3G), a host cytidine deaminase that can block HIV-1 replication. Abrogation of A3G function involves the HIV-1 Vif protein, which binds A3G and serves as an adapter molecule to recruit A3G to a Cullin5-based E3 ubiquitin ligase complex. Structure-guided mutagenesis of A3G focused on the 14 most surface-exposed Lys residues allowed us to identify four Lys residues (Lys-297, 301, 303, and 334) that are required for Vif-mediated A3G ubiquitination and degradation. Substitution of Arg for these residues confers Vif resistance and restores A3G's antiviral activity in the presence of Vif. In our model, the critical four Lys residues cluster at the C terminus, opposite to the known N-terminal Vif-interaction region in the protein. Thus, spatial constraints imposed by the E3 ligase complex may be an important determinant in Vif-dependent A3G ubiquitination.
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