Vif

The accessory protein Vif acts early in the viral lifecycle to inactivate cellular cytidine deaminases A3F and A3G (members of the APOBEC3 family) that would otherwise cause rampant incorporation of deoxyuridines into the viral genome, leading to a high mutation rate and destroying key viral functions. Vif recruits A3G and A3F to a cellular ubiquitin protein ligase (E3 ligase) that includes Cullin-5, Ring-box 1 and Elongins B and C, ultimately leading to ubiquitination of A3G and A3F and their destruction by the proteosome.

The HARC Center Vif project, headed by Dr. B. Matija Peterlin and Dr. John Gross, is an extension of Dr. Peterlin's previous work on the Vif/APOBEC system, including characterization of the interactions between APOBEC proteins and Vif, as well as establishing the substrate specificities of A3G and A3F and demonstrating the importance of APOBEC proteins in inhibiting viral replication in mice. Combined with the structural expertise of Dr. Gross and other HARC Center members, this sets the stage for detailed structural/functional analysis of Vif and its macromolecular partners.

The Vif project aims to elucidate the structural nature of Vif-mediated interactions that target APOBEC cytidine deaminases for destruction by the proteasome, as well as to better understand the antiviral activity of the APOBEC proteins themselves. The Vif project thus involves comprehensive analysis of Vif with its various protein partners in large complexes, or subcomplexes, as well as in the presence of nucleic acids, and utilizes the full array of structural resources available in the HARC Center, from x-ray crystallography to NMR and cryo-EM.