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.
- MeSH
- dimerizace MeSH
- Escherichia coli MeSH
- histonlysin-N-methyltransferasa metabolismus MeSH
- HIV-integrasa metabolismus MeSH
- konsenzuální sekvence MeSH
- Lentivirus enzymologie MeSH
- lidé MeSH
- mezibuněčné signální peptidy a proteiny metabolismus MeSH
- molekulární sekvence - údaje MeSH
- proteiny metabolismus MeSH
- protoonkogenní protein MLL metabolismus MeSH
- represorové proteiny metabolismus MeSH
- sekvence aminokyselin MeSH
- terciární struktura proteinů MeSH
- transposasy metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
