Lens epithelium-derived growth factor (LEDGF) is a chromatin-associated protein implicated in leukemia and HIV type 1 infection. LEDGF associates with mixed-lineage leukemia (MLL) fusion proteins andmenin and is required for leukemic transformation. To better understand themolecular mechanismunderlying the LEDGF integrase-binding domain (IBD) interaction with MLL fusion proteins in leukemia, we determined the solution structure of the MLL-IBD complex. We found a novel MLLmotif, integrase domain bindingmotif 2 (IBM2), which binds to a well-defined site on IBD. Point mutations within IBM2 abolished leukemogenic transformation by MLL-AF9, validating that this newly identified motif is essential for the oncogenic activityofMLLfusionproteins. Interestingly, the IBM2bindingsiteon IBDoverlaps with the binding site for the HIV integrase (IN), and IN was capable of efficiently sequestering IBD fromthemenin-MLL complex.Ashort IBM2 peptidebinds to IBDdirectly andinhibitsboth the IBD-MLL/menin and IBD-IN interactions. Our findings show that the same site on IBD is involved in binding to MLL and HIV-IN, revealing an attractive approach to simultaneously target LEDGF in leukemia and HIV.
ASJC Scopus subject areas
- Cell Biology