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Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation
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SYSNO ASEP 0495066 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation Author(s) Sharma, S. (BE)
Čermáková, K. (CZ)
De Rijck, J. (BE)
Demeulemeester, J. (BE)
Fábry, Milan (UMG-J) RID
El Ashkar, S. (BE)
Van Belle, S. (BE)
Lepšík, M. (CZ)
Těšina, Petr (UMG-J)
Duchoslav, V. (CZ)
Novák, P. (CZ)
Hubálek, M. (CZ)
Srb, P. (CZ)
Christ, F. (BE)
Řezáčová, Pavlína (UMG-J) RID
Hodges, H. C. (US)
Debyser, Z. (BE)
Veverka, V. (CZ)Number of authors 18 Source Title Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences - ISSN 0027-8424
Roč. 115, č. 30 (2018), E7053-E7062Number of pages 10 s. Language eng - English Country US - United States Keywords LEDGF/p75 ; disordered proteins ; protein-protein interactions ; phosphorylation ; leukemia Subject RIV EB - Genetics ; Molecular Biology OECD category Biochemistry and molecular biology Institutional support UMG-J - RVO:68378050 UT WOS 000439574700012 DOI 10.1073/pnas.1803909115 Annotation 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. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2019
Number of the records: 1