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

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

doi:https://dx.doi.org/10.1073/pnas.1803909115

Number of the records: 1

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

1.

SYSNO ASEP	0492184
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, Kateřina (UOCHB-X)_ORCID De Rijck, J. (BE) Demeulemeester, J. (BE) Fábry, M. (CZ) El Ashkar, S. (BE) Van Belle, S. (BE) Lepšík, Martin (UOCHB-X)_{RID, ORCID} Těšina, Petr (UOCHB-X) Duchoslav, Vojtěch (UOCHB-X) Novák, Petr (MBU-M)_{RID, ORCID} Hubálek, Martin (UOCHB-X)_{RID, ORCID} Srb, Pavel (UOCHB-X)_{RID, ORCID} Christ, F. (BE) Řezáčová, Pavlína (UOCHB-X)_{RID, ORCID} Hodges, H. C. (US) Debyser, Z. (BE) Veverka, Václav (UOCHB-X)_{RID, ORCID}
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-E7062
Number of pages	10 s.
Language	eng - English
Country	US - United States
Keywords	LEDGF/p75 ; disordered proteins ; protein-protein interactions ; phosphorylation ; leukemia
Subject RIV	CE - Biochemistry
OECD category	Biochemistry and molecular biology
R&D Projects	LO1304 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
	LK11205 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
	GA16-06357S GA ČR - Czech Science Foundation (CSF)
	EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
Institutional support	UOCHB-X - RVO:61388963 ; MBU-M - RVO:61388971
UT WOS	000439574700012
EID SCOPUS	85052021815
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 Organic Chemistry and Biochemistry
Contact	asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418
Year of Publishing	2019

Number of the records: 1