Structural and Functional Insights into Foamy Viral Integrase

Abstract

Successful integration of retroviral DNA into the host chromosome is an essential step for viral replication. The process is mediated by virally encoded integrase (IN) and orchestrated by 3'-end processing and the strand transfer reaction. In vitro reaction conditions, such as substrate specificity, cofactor usage, and cellular binding partners for such reactions by the three distinct domains of prototype foamy viral integrase (PFV-IN) have been described well in several reports. Recent studies on the three‑dimensional structure of the interacting complexes between PFV-IN and DNA, cofactors, binding partners, or inhibitors have explored the mechanistic details of such interactions and shown its utilization as an important target to develop anti-retroviral drugs. The presence of a potent, non-transferable nuclear localization signal in the PFV C-terminal domain extends its use as a model for investigating cellular trafficking of large molecular complexes through the nuclear pore complex and also to identify novel cellular targets for such trafficking. This review focuses on recent advancements in the structural analysis and in vitro functional aspects of PFV-IN.

Insight into the ERVK Integrase – Propensity for DNA Damage

“…This catalytic triad recognizes and binds to Mg 2+ which is essential for proper IN function and multimerization (reviewed in Lesbats et al, 2016). The acidic residues of the DDE motif catalyze 3′ linear DNA processing, DNA strand transfer reactions, and disintegration reactions (reverse of the strand transfer ligation reaction) – all enzymatic processes required for a functional IN (Hossain et al, 2013; Wolkowicz et al, 2014). The CTD is the least conserved domain, although it contains some conserved tryptophan residues, and is integral to the formation of the intasome (reviewed in Lesbats et al, 2016).…”

Catalytic Mechanism of Retroviral Integrase for the Strand Transfer Reaction Explored by QM/MM Calculations

“…Furthermore, their enzymatic activity is remarkably similar. 33 Thus, PFV IN is considered a model system to study the catalytic mechanism of HIV-1 IN as well as the interaction with HIV-1 IN inhibitors. 32,34,35 Retroviral IN proteins have three common domains: a Nterminal domain (NTD), the catalytic core domain (CCD), which includes the active site, and the C-terminal domain (CTD).…”

“…PFV IN has only 15% sequence similarity with HIV-1 IN, but the similarity increases to 22% when considering only the catalytic core domain. Furthermore, their enzymatic activity is remarkably similar . Thus, PFV IN is considered a model system to study the catalytic mechanism of HIV-1 IN as well as the interaction with HIV-1 IN inhibitors. ,, …”