PNAS 2018
LEDGF/p75 IBD binding partners interact in a structurally conserved manner. Solution structures of the IBD in complex with the binding motifs from POGZ, JPO2 motif 1 and 2 (M1, M2), IWS1, and MLL1 determined by NMR spectroscopy.
Zeger Debyser and Václav Veverka Research Groups
Significance
The transcription coactivator LEDGF/p75 contributes to regulation of gene expression by tethering other factors to actively transcribed genes on chromatin. Its chromatin-tethering activity is hijacked in two important disease settings, HIV and mixed-lineage leukemia; however, the basis for the biological regulation of LEDGF/p75’s interaction to binding partners has remained unknown. This has represented a gap in our understanding of LEDGF/p75’s fundamental biological function and a major limitation for development of therapeutic targeting of LEDGF/p75 in human disease. Our work provides a mechanistic understanding of how the lens epithelium-derived growth factor interaction network is regulated at the molecular level. We reveal that structurally conserved IBD-binding motifs (IBMs) on known LEDGF/p75 binding partners can be regulated by phosphorylation, permitting switching between low- and high-affinity states. Finally, we show that elimination of IBM phosphorylation sites on MLL1 disrupts the oncogenic potential of primary MLL1-rearranged leukemic cells. Our results demonstrate that kinase-dependent phosphorylation of MLL1 represents a previously unknown oncogenic dependency that may be harnessed in the treatment of MLL-rearranged leukemia.
Sharma, S. et. al.: Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation, PNAS 2018, 115 (30) E7053-E7062.doi.org/10.1073/pnas.1803909115