期刊
NATURE COMMUNICATIONS
卷 6, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms8968
关键词
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资金
- FP7 framework of the European Union (THINC) [HEALTH-2007-2.3.2-1]
- Ministry of Education of the Czech Republic [LK11205, 7E08066, LO1304, LO1302]
- Academy of Sciences of the Czech Republic [RVO 61388963, 68378050]
- Charles University in Prague [GA UK 200213, SVV-2015-260209]
- Research Foundation Flanders [G.0595.13, KAN2012 1.5.108.12]
- Flemish agency for Innovation by Science and Technology (IWT) SBO Interactomics [QPG-345523]
- IAP BelVir
- KU Leuven research fund [IDO/12/008]
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.
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