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Abstract
BackgroundThe virion infectivity factor (Vif) is an accessory protein, which is essential for HIV replication in host cells. Vif neutralizes the antiviral host protein APOBEC3 through recruitment of the E3 ubiquitin ligase complex.MethodologyFifty thousand Vif models were generated using the ab initio relax protocol of the Rosetta algorithm from sets of three- and nine-residue fragments using the fragment Monte Carlo insertion-simulated annealing strategy, which favors protein-like features, followed by an all-atom refinement. In the protocol, a constraints archive was used to define the spatial relationship between the side chains from Cys/His residues and zinc ions that formed the zinc-finger motif that is essential for Vif function. We also performed centroids analysis and structural analysis with respect to the formation of the zinc-finger, and the residue disposal in the protein binding domains. Additionally, molecular docking was used to explore details of Vif-A3G and Vif-EloBC interactions. Furthermore, molecular dynamics simulation was used to evaluate the stability of the complexes Vif-EloBC-A3G and Vif-EloC.Principal FindingsThe zinc in the HCCH domain significantly alters the folding of Vif and changes the structural dynamics of the HCCH region. Ab initio modeling indicated that the Vif zinc-finger possibly displays tetrahedral geometry as suggested by Mehle et al. (2006). Our model also showed that the residues L146 and L149 of the BC-box motif bind to EloC by hydrophobic interactions, and the residue P162 of the PPLP motif is important to EloB binding.Conclusions/SignificanceThe model presented here is the first complete three-dimensional structure of the Vif. The interaction of Vif with the A3G protein and the EloBC complex is in agreement with empirical data that is currently available in the literature and could therefore provide valuable structural information for advances in rational drug design.
Highlights
The Virion Infectivity Factor (Vif) is an accessory protein, which is essential for HIV replication
A sequence of 15 residues (178–192) of the C-terminus region was removed [69]. None of these models incorporated data of the HCCH domain that is crucial for Cul5 interaction and for virion infectivity factor (Vif) folding. These models were proposed before empirical evidences, based on X-ray diffraction, showing the recruitment of the E3 ubiquitin ligase complex by the Vif BC-box motif [23]
This study has focused on the binding domains of the APOBEC3/E3 ubiquitin ligase complex, Vif displays other biological functions
Summary
The Virion Infectivity Factor (Vif) is an accessory protein, which is essential for HIV replication. It is important be pointed out that Vif has many others important biological functions for HIV life cycle such as: G2 cell cycle arrest, suppression of A3G protein synthesis, inhibition of A3G packaging into the virus particles and RNA chaperone activity [15,16,17,18,19,20]. We would like to mention that the structure of Vif and its interaction with APOBEC3G and other proteins of the E3 ubiquitin ligase complex have been extensively studied owing to the potential drug-oriented therapy [21]. The virion infectivity factor (Vif) is an accessory protein, which is essential for HIV replication in host cells. Vif neutralizes the antiviral host protein APOBEC3 through recruitment of the E3 ubiquitin ligase complex
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