MRC National Institute for Medical Research, London
Science for Health
A spumaviral Gag-Env complex
10 May 2013
Structural and virological studies by NIMR scientists have revealed the nature of an essential Gag-Env interaction that is required for spumaretrovirus egress from the cell. The research is published in PLOS Pathogens.
The Spumaretrovirinae, or foamyviruses (FVs), are complex retroviruses that infect many species of monkey and ape. They derive their name from the cytopathic effects they cause in cell culture. Even though FVs are endemic within non-human primates and display a broad host range, human-to-human transmission of PFV has never been detected. However, 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. Importantly, infection in humans is apparently benign, making their usage as vectors for gene therapy an attractive proposition.
FVs share many similarities with other retroviruses in respect of their genome organisation and life cycle. 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.
In order to probe the functional overlap of FV and orthoretroviral Gag and learn more about FV egress and replication Ian Taylor, from NIMR’s Division of Molecular Structure, and Jonathan Stoye, from the Division of Virology, have undertaken a structural, biophysical and virological study of PFV-Gag. They have solved 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. Based on these structures, further combined mutagenesis, biochemical and virological studies were then used to probe and reveal the molecular details of the essential Gag-Env interaction.
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. These findings have important implications for the evolution of FVs and the mechanism of virus restriction by Trim5α.
Ian Taylor
Structure of the PFV Gag-Env complex shown in cartoon representation.
Click image to view at full-size
The monomers of the Gag-NtD homodimer are coloured green and blue. The helical Env peptides bound at the periphery of each head domain are coloured magenta and gold.
Original article
David C. Goldstone, Thomas G. Flower, Neil J. Ball, Marta Sanz-Ramos, Melvyn W. Yap, Roksana W. Ogrodowicz, Nicole Stanke, Juliane Reh, Dirk Lindemann, Jonathan P. Stoye and Ian A. Taylor (2013)
A unique spumavirus Gag N-terminal domain with functional properties of orthoretroviral Matrix and Capsid
PLOS Pathogens, 9(5): e1003376. Article fulltext.
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