title: Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif.
abstract: 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.
authors.affiliation: Institute of Organic Chemistry and Biochemistry of the ASCR, v.v.i., Flemingovo nam. 2, 166 10 Prague, Czech Republic.|Department of Genetics and Microbiology, Faculty of Science, Charles University in Prague, Vinicna 5, 128 44 Prague, Czech Republic.|Institute of Molecular Genetics of the ASCR, v.v.i., Videnska 1083, 142 20 Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Tesina
authors.affiliation: KU Leuven, Molecular Virology and Gene Therapy, Kapucijnenvoer 33, B-3000 Leuven, Belgium.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Čermáková
authors.affiliation: Institute of Molecular Genetics of the ASCR, v.v.i., Videnska 1083, 142 20 Prague, Czech Republic.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Hořejší
authors.affiliation: Institute of Organic Chemistry and Biochemistry of the ASCR, v.v.i., Flemingovo nam. 2, 166 10 Prague, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Procházková
authors.affiliation: Institute of Molecular Genetics of the ASCR, v.v.i., Videnska 1083, 142 20 Prague, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Fábry
authors.affiliation: KU Leuven, Molecular Virology and Gene Therapy, Kapucijnenvoer 33, B-3000 Leuven, Belgium.
authors.forename: Subhalakshmi
authors.initials: S
authors.lastname: Sharma
authors.affiliation: KU Leuven, Molecular Virology and Gene Therapy, Kapucijnenvoer 33, B-3000 Leuven, Belgium.
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.affiliation: KU Leuven, Molecular Virology and Gene Therapy, Kapucijnenvoer 33, B-3000 Leuven, Belgium.
authors.forename: Jonas
authors.initials: J
authors.lastname: Demeulemeester
authors.affiliation: KU Leuven, Molecular Virology and Gene Therapy, Kapucijnenvoer 33, B-3000 Leuven, Belgium.
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.affiliation: KU Leuven, Molecular Virology and Gene Therapy, Kapucijnenvoer 33, B-3000 Leuven, Belgium.
authors.forename: Jan De
authors.initials: J
authors.lastname: Rijck
authors.affiliation: Institute of Organic Chemistry and Biochemistry of the ASCR, v.v.i., Flemingovo nam. 2, 166 10 Prague, Czech Republic.
authors.forename: Václav
authors.initials: V
authors.lastname: Veverka
authors.affiliation: Institute of Organic Chemistry and Biochemistry of the ASCR, v.v.i., Flemingovo nam. 2, 166 10 Prague, Czech Republic.|Institute of Molecular Genetics of the ASCR, v.v.i., Videnska 1083, 142 20 Prague, Czech Republic.
authors.forename: Pavlína
authors.initials: P
authors.lastname: Řezáčová
mesh_terms: D000595:Amino Acid Sequence; D016384:Consensus Sequence; D019281:Dimerization; D004926:Escherichia coli; D019427:HIV Integrase / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D016086:Lentivirus / Q000201:enzymology; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D016601:RNA-Binding Proteins; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors; D019895:Transposases / Q000378:metabolism*; D004268:DNA-Binding Proteins; D018797:Cell Cycle Proteins
chemical_list: D019427:HIV Integrase; D011495:Histone-Lysine N-Methyltransferase; D036341:Intercellular Signaling Peptides and Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D011506:Proteins; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D019895:Transposases; C513450:CDCA7L protein, human; C510636:Iws1 protein, human; C497422:KMT2A protein, human; C541037:POGZ protein, human; D004268:DNA-Binding Proteins; D018797:Cell Cycle Proteins; C119380:lens epithelium-derived growth factor