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Sharma, Subhalakshmi; Cermakova, Katerina; Rijck, Jan de; Demeulemeester, Jonas; Fabry, Milan; El Ashkar, Sara; Belle, Siska van; Lepsik, Martin; Tesina, Petr; Duchoslav, Vojtech; Novak, Petr; Hubalek, Martin; Srb, Pavel; Christ, Frauke; Rezacova, Pavlina; Hodges, H. Courtney; Debyser, Zeger; Veverka, Vaclav (2018): Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation. In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 30, E7053-E7062
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Abstract

Lens epithelium-derived growth factor/p75 (LE DGF/p75, or PSIP1) is a transcriptional coactivator that tethers other proteins to gene bodies. The chromatin tethering function of LEDGF/p75 is hijacked by HIV integrase to ensure viral integration at sites of active transcription. LEDGF/p75 is also important for the development of mixed-lineage leukemia (MLL), where it tethers the MLL1 fusion complex at aberrant MLL targets, inducing malignant transformation. However, little is known about how the LEDGF/p75 protein interaction network is regulated. Here, we obtained solution structures of the complete interfaces between the LEDGF/p75 integrase binding domain (IBD) and its cellular binding partners and validated another binding partner, Mediator subunit 1 (MED1). 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.