Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif

0454556 - ÚOCHB 2016 RIV GB eng J - Journal Article
Těšina, Petr - Čermáková, K. - Hořejší, M. - Procházková, Kateřina - Fábry, M. - Sharma, S. - Christ, F. - Demeulemeester, J. - Debyser, Z. - De Rijck, J. - Veverka, Václav - Řezáčová, Pavlína
Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif.
Nature Communications. Roč. 6, Aug (2015), č. článku 7968. E-ISSN 2041-1723
R&D Projects: GA MŠMT(CZ) LK11205; GA MŠMT(CZ) 7E08066; GA MŠMT(CZ) LO1304; GA MŠMT LO1302
EU Projects: European Commission(XE) 201032 - THINC
Institutional support: RVO:61388963
Keywords : LEDGF/p75 * PogZ * JPO2 * PSIP1 * IWS1 * H3K36me3 * integrase
OECD category: Biochemistry and molecular biology
Impact factor: 11.329, year: 2015

Lens epithelium-derived growth factor (LEDGF/p75) is an epigenetic reader and attractive therapeutic target involved in HIV integration and the development of mixed lineage leukaemia (MLL1) fusion-driven leukaemia. Besides HIV integrase and the MLL1-menin complex, LEDGF/p75 interacts with various cellular proteins via its integrase binding domain (IBD). Here we present structural characterization of IBD interactions with transcriptional repressor JPO2 and domesticated transposase PogZ, and show that the PogZ interaction is nearly identical to the interaction of LEDGF/p75 with MLL1. The interaction with the IBD is maintained by an intrinsically disordered IBD-binding motif (IBM) common to all known cellular partners of LEDGF/p75. In addition, based on IBM conservation, we identify and validate IWS1 as a novel LEDGF/p75 interaction partner. Our results also reveal how HIV integrase efficiently displaces cellular binding partners from LEDGF/p75. Finally, the similar binding modes of LEDGF/p75 interaction partners represent a new challenge for the development of selective interaction inhibitors.
Permanent Link: http://hdl.handle.net/11104/0255233