Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif

Petr Tesina, Kateřina Čermáková, Magdalena Hořejší, Kateřina Procházková, Milan Fábry, Subhalakshmi Sharma, Frauke Christ, Jonas Demeulemeester, Zeger Debyser, Jan De Rijck (), Václav Veverka () and Pavlína Řezáčová ()
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Petr Tesina: Institute of Organic Chemistry and Biochemistry of the ASCR
Kateřina Čermáková: KU Leuven, Molecular Virology and Gene Therapy
Magdalena Hořejší: Institute of Molecular Genetics of the ASCR
Kateřina Procházková: Institute of Organic Chemistry and Biochemistry of the ASCR
Milan Fábry: Institute of Molecular Genetics of the ASCR
Subhalakshmi Sharma: KU Leuven, Molecular Virology and Gene Therapy
Frauke Christ: KU Leuven, Molecular Virology and Gene Therapy
Jonas Demeulemeester: KU Leuven, Molecular Virology and Gene Therapy
Zeger Debyser: KU Leuven, Molecular Virology and Gene Therapy
Jan De Rijck: KU Leuven, Molecular Virology and Gene Therapy
Václav Veverka: Institute of Organic Chemistry and Biochemistry of the ASCR
Pavlína Řezáčová: Institute of Organic Chemistry and Biochemistry of the ASCR

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8968

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