Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation

0492184 - ÚOCHB 2019 RIV US eng J - Journal Article
Sharma, S. - Čermáková, Kateřina - De Rijck, J. - Demeulemeester, J. - Fábry, M. - El Ashkar, S. - Van Belle, S. - Lepšík, Martin - Těšina, Petr - Duchoslav, Vojtěch - Novák, Petr - Hubálek, Martin - Srb, Pavel - Christ, F. - Řezáčová, Pavlína - Hodges, H. C. - Debyser, Z. - Veverka, Václav
Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation.
Proceedings of the National Academy of Sciences of the United States of America. Roč. 115, č. 30 (2018), E7053-E7062. ISSN 0027-8424. E-ISSN 1091-6490
R&D Projects: GA MŠMT(CZ) LO1304; GA MŠMT(CZ) LK11205; GA ČR(CZ) GA16-06357S; GA MŠMT(CZ) EF16_019/0000729
Institutional support: RVO:61388963 ; RVO:61388971
Keywords : LEDGF/p75 * disordered proteins * protein-protein interactions * phosphorylation * leukemia
OECD category: Biochemistry and molecular biology
Impact factor: 9.580, year: 2018

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.
Permanent Link: http://hdl.handle.net/11104/0285739