Abstract:
In most cases, proteolytic processing of the retroviral Pol portion of the Gag-Pol polyprotein
precursor produces protease (PR), reverse transcriptase (RT), and integrase (IN). However, foamy
viruses (FVs) express Pol separately from Gag and, when Pol is processed, only the IN domain is
released. Here, we report a 2.9 Å resolution crystal structure of the mature PR-RT from prototype FV
(PFV) that can carry out both proteolytic processing and reverse transcription but is in a configuration
not competent for proteolytic or polymerase activity. PFV PR-RT is monomeric and the architecture
of PFV PR is similar to one of the subunits of HIV-1 PR, which is a dimer. There is a C-terminal
extension of PFV PR (101-145) that consists of two helices which are adjacent to the base of the RT
palm subdomain, and anchors PR to RT. The polymerase domain of PFV RT consists of fingers,
palm, thumb, and connection subdomains whose spatial arrangements are similar to the p51 subunit
of HIV-1 RT. The RNase H and polymerase domains of PFV RT are connected by flexible linkers.
Significant spatial and conformational (sub)domain rearrangements are therefore required for nucleic
acid binding. The structure of PFV PR-RT provides insights into the conformational maturation of
retroviral Pol polyproteins.
