Cryo-em structure of the delta-retroviral intasome in complex with the pp2a regulatory subunit b56γ

The Retroviridae delta-retrovirus genus includes the most oncogenic pathogen– human T-cell lymphotropic virus type 1 (HTLV-1)([1][1]). Many of the ~20 million people infected with HTLV-1 will develop severe leukaemia ([2][2]) or an ALS-like motor disease ([3][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 B56γ subunit of its human host factor, the protein phosphatase 2A ([4][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 B56γ 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. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4