Abstract
The Spumaretrovirinae, or foamyviruses (FVs) are complex retroviruses that infect many species of monkey and ape. Although FV infection is apparently benign, trans-species zoonosis is commonplace and has resulted in the isolation of the Prototypic Foamy Virus (PFV) from human sources and the potential for germ-line transmission. Despite little sequence homology, FV and orthoretroviral Gag proteins perform equivalent functions, including genome packaging, virion assembly, trafficking and membrane targeting. In addition, PFV Gag interacts with the FV Envelope (Env) protein to facilitate budding of infectious particles. Presently, there is a paucity of structural information with regards FVs and it is unclear how disparate FV and orthoretroviral Gag molecules share the same function. Therefore, in order to probe the functional overlap of FV and orthoretroviral Gag and learn more about FV egress and replication we have undertaken a structural, biophysical and virological study of PFV-Gag. We present the crystal structure of a dimeric amino terminal domain from PFV, Gag-NtD, both free and in complex with the leader peptide of PFV Env. The structure comprises a head domain together with a coiled coil that forms the dimer interface and despite the shared function it is entirely unrelated to either the capsid or matrix of Gag from other retroviruses. Furthermore, we present structural, biochemical and virological data that reveal the molecular details of the essential Gag-Env interaction and in addition we also examine the specificity of Trim5α restriction of PFV. These data provide the first information with regards to FV structural proteins and suggest a model for convergent evolution of gag genes where structurally unrelated molecules have become functionally equivalent.
Highlights
Spuma- or foamy viruses (FVs) are complex retroviruses and constitute the only members of the Spumaretrovirinae subfamily within the Retroviridae family
Terminal 179 residues of Prototypic foamy virus (PFV)-Gag comprised a stable domain (PFV-Gag-NtD). This fragment was expressed in E. coli and subsequently the crystal structure determined by single wavelength anomalous diffraction (SAD) methods and refined at a resolution of 2.4 A
Helix a5 is immediately followed by a6, a long helix (58 A ) comprising residues Arg140-Ser179 that forms the coiled coil domain making the majority of interactions between the two monomers. The observation of this unusual arrangement prompted us to examine the structural relatedness of the PFV-Gag-NtD with the Gagderived proteins from other retroviruses and those of hepadna
Summary
Spuma- or foamy viruses (FVs) are complex retroviruses and constitute the only members of the Spumaretrovirinae subfamily within the Retroviridae family. They have been isolated from a variety of primate hosts [1,2,3,4] as well as from cats [5,6,7], cattle [8], horses [9] and sheep [10]. The PFV genome is highly similar to that of isolates of simian foamy virus from chimpanzee (SFVcpz) and so infection in humans is believed to have arisen through a zoonotic transmission [16,17,18]. In cell culture FV infection causes pronounced cytopathic effects [19] infection in humans is apparently asymptomatic [20,21,22] making their usage as vectors for gene therapy an attractive proposition [23]
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