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Cell Rep. 2015 Dec 1;13(9):1781-8. doi: 10.1016/j.celrep.2015.10.067. Epub 2015 Nov 25.

The Binding Interface between Human APOBEC3F and HIV-1 Vif Elucidated by Genetic and Computational Approaches.

Author information

1
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
2
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
3
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
4
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; Institute for Molecular Virology, University of Minnesota, Minneapolis, MN 55455, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Howard Hughes Medical Institute, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: rsh@umn.edu.

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.

KEYWORDS:

APOBEC3F; APOBEC3F-Vif interface; HIV-1; Vif; pathogen-host interaction

PMID:
26628363
PMCID:
PMC4684092
DOI:
10.1016/j.celrep.2015.10.067
[Indexed for MEDLINE]
Free PMC Article

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