title: The same site on the integrase-binding domain of lens epithelium-derived growth factor is a therapeutic target for MLL leukemia and HIV.
abstract: 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 and menin and is required for leukemic transformation. To better understand the molecular mechanism underlying 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 MLL motif, integrase domain binding motif 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 activity of MLL fusion proteins. Interestingly, the IBM2 binding site on IBD overlaps with the binding site for the HIV integrase (IN), and IN was capable of efficiently sequestering IBD from the menin-MLL complex. A short IBM2 peptide binds to IBD directly and inhibits both 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.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Murai
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Pollock
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: Shihan
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Miao
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: Trupta
authors.initials: T
authors.lastname: Purohit
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: Adam
authors.initials: A
authors.lastname: Yokom
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: Jay L
authors.initials: JL
authors.lastname: Hess
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Muntean
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Grembecka
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Cierpicki
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D057809:HEK293 Cells; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D019427:HIV Integrase / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D047468:Immunoprecipitation; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015456:Leukemia, Biphenotypic, Acute / Q000188:drug therapy / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; C497422:KMT2A protein, human; C105373:MEN1 protein, human; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; C119380:lens epithelium-derived growth factor; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D019427:HIV Integrase