Interactome and structural basis for targeting the human T-cell leukemia virus Tax oncoprotein

Human T-cell leukemia virus type-1 (HTLV-1) is the first pathogenic retrovirus discovered in human. Although HTLV-1-induced diseases are well characterized and linked to the encoded Tax-1 protein, there is currently no strategy to target Tax-1 functions with small molecules. Here, we report a comprehensive interaction map between Tax-1 and human PDZ domain-containing proteins (hPDZome), and we show that Tax-1 interacts with one-third of them. This includes proteins involved in cell cycle, cell-cell junction and cytoskeleton organization, as well as in membrane complexes assembly. Using nuclear magnetic resonance (NMR) spectroscopy, we have determined the structural basis of the interaction between the C-terminal PDZ binding motif (PBM) of Tax-1, and the PDZ domains of DLG1 and syntenin-1. Finally, we have used molecular modeling and mammalian cell-based assays to demonstrate that Tax-1/PDZ-domain interactions are amenable to small-molecule inhibition. Thus, our work provides a framework for the design of targeted therapies for HTLV-1-induced diseases. HighlightsO_LIcomprehensive interactome map of HTLV-1 Tax / human PDZ proteins C_LIO_LIbasis of Tax-1 PBM binding to human DLG1 and syntenin-1 PDZ domains". C_LIO_LIsignificance of inhibiting Tax-1 functions C_LIO_LIof the Tax-1 / PDZ interface C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/457680v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@6ba754org.highwire.dtl.DTLVardef@1b68124org.highwire.dtl.DTLVardef@d873c6org.highwire.dtl.DTLVardef@98f7ae_HPS_FORMAT_FIGEXP M_FIG C_FIG