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bioRxiv · 10.1101/2020.06.19.161513

CRYO-EM STRUCTURE OF THE DELTA-RETROVIRAL INTASOME IN COMPLEX WITH THE PP2A REGULATORY SUBUNIT B56gamma

Barski, M. S.·Minnell, J. J.·Hodakova, Z.·Pye, V.·Nans, A.·Cherepanov, P.·Maertens, G. N.
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Abstract

The Retroviridae delta-retrovirus genus includes the most oncogenic pathogen- human T-cell lymphotropic virus type 1 (HTLV-1)(1). Many of the ~20 million people infected with HTLV-1 will develop severe leukaemia (2) or an ALS-like motor disease (3) unless a therapy becomes available. A key step in the establishment of infection is the integration of viral genetic material into the host genome, catalysed by the viral integrase (IN) enzyme. Here we used X-ray crystallography and single-particle cryo-electron microscopy to determine the structure of functional delta-retroviral IN assembled on viral DNA ends and bound the B56{gamma} subunit of its human host factor, the protein phosphatase 2A (4). The structure reveals a tetrameric IN assembly bound to the phosphatase via a conserved short linear motif found within the extended linker connecting the catalytic core (CCD) and C-terminal (CTD) IN domains. Unexpectedly, all four IN subunits are involved in B56{gamma} binding, taking advantage of the flexibility of the CCD-CTD linkers. Our results fill the current gap in the structural understanding of the delta-retroviral integration machinery. Insight into the interactions between the delta-retroviral intasome and the host will be crucial for understanding the pattern of integration events in infected individuals and therefore bears important clinical implications.

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Barski, M. S., Minnell, J. J., Hodakova, Z., Pye, V., Nans, A., Cherepanov, P., Maertens, G. N.. 2020-06-20. CRYO-EM STRUCTURE OF THE DELTA-RETROVIRAL INTASOME IN COMPLEX WITH THE PP2A REGULATORY SUBUNIT B56gamma. https://doi.org/10.1101/2020.06.19.161513

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