Abstract
APOBEC3 family DNA cytosine deaminases provide overlapping defenses against pathogen infections. However, most viruses have elaborate evasion mechanisms such as the HIV-1 Vif protein, which subverts cellular CBF-β and a polyubiquitin ligase complex to neutralize these enzymes. Despite advances in APOBEC3 and Vif biology, a full understanding of this direct host-pathogen conflict has been elusive. We combine virus adaptation and computational studies to interrogate the APOBEC3F-Vif interface and build a robust structural model. A recurring compensatory amino acid substitution from adaptation experiments provided an initial docking constraint, and microsecond molecular dynamic simulations optimized interface contacts. Virus infectivity experiments validated a long-lasting electrostatic interaction between APOBEC3F E289 and HIV-1 Vif R15. Taken together with mutagenesis results, we propose a wobble model to explain how HIV-1 Vif has evolved to bind different APOBEC3 enzymes and, more generally, how pathogens may evolve to escape innate host defenses.
Original language | English (US) |
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Pages (from-to) | 1781-1788 |
Number of pages | 8 |
Journal | Cell Reports |
Volume | 13 |
Issue number | 9 |
DOIs | |
State | Published - Dec 1 2015 |
Externally published | Yes |
Keywords
- APOBEC3F
- APOBEC3F-Vif interface
- HIV-1
- Pathogen-host interaction
- Vif
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology