CRYO EM STRUCTURE OF THE DELTA RETROVIRAL INTASOME IN COMPLEX WITH THE PP2A REGULATORY SUBUNIT B56g
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 B56g 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 B56g 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.