Article

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

  • Nature Communications 6, Article number: 7968 (2015)
  • doi:10.1038/ncomms8968
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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.

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Acknowledgements

We would like to thank Milan Kozisek, Lucie Bednarova and Radko Soucek (IOCB AS CR) for their help with collecting, processing and analysing ITC and CD data and with amino-acid analysis. We also thank Martine Michiels for excellent technical assistance. This work was supported by a grant from the FP7 framework of the European Union (THINC, HEALTH-2007-2.3.2-1); the Ministry of Education of the Czech Republic—LK11205 (programme ‘NAVRAT’), 7E08066, LO1304 (programme ‘NPU I’) and Project InterBioMed LO1302; the Academy of Sciences of the Czech Republic, projects RVO 61388963 and 68378050 and Charles University in Prague, project GA UK 200213 and SVV-2015-260209. The Research Foundation Flanders, G.0595.13 and KAN2012 1.5.108.12; the Flemish agency for Innovation by Science and Technology (IWT) SBO Interactomics, QPG-345523; the IAP BelVir and the KU Leuven research fund, IDO/12/008, also provided support.

Author information

Author notes

    • Petr Tesina
    •  & Kateřina Čermáková

    These authors contributed equally to the manuscript

    • Jan De Rijck
    • , Václav Veverka
    •  & Pavlína Řezáčová

    These authors jointly supervised this work

Affiliations

  1. Institute of Organic Chemistry and Biochemistry of the ASCR, v.v.i., Flemingovo nam. 2, 166 10 Prague, Czech Republic

    • Petr Tesina
    • , Kateřina Procházková
    • , Václav Veverka
    •  & Pavlína Řezáčová
  2. Department of Genetics and Microbiology, Faculty of Science, Charles University in Prague, Vinicna 5, 128 44 Prague, Czech Republic

    • Petr Tesina
  3. Institute of Molecular Genetics of the ASCR, v.v.i., Videnska 1083, 142 20 Prague, Czech Republic

    • Petr Tesina
    • , Magdalena Hořejší
    • , Milan Fábry
    •  & Pavlína Řezáčová
  4. KU Leuven, Molecular Virology and Gene Therapy, Kapucijnenvoer 33, B-3000 Leuven, Belgium

    • Kateřina Čermáková
    • , Subhalakshmi Sharma
    • , Frauke Christ
    • , Jonas Demeulemeester
    • , Zeger Debyser
    •  & Jan De Rijck

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Contributions

P.T., K.C., K.P., M.H., M.F., S.S., J.D., J.D.R. and V.V. performed experiments and analysed the data. P.T., K.C., Z.D., J.D.R., F.C., V.V. and P.R. designed the experiments and interpreted the data. P.T., K.C., J.D.R., V.V. and P.R. wrote the manuscript. Z.D. corrected the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jan De Rijck or Václav Veverka or Pavlína Řezáčová.

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    Supplementary Information

    Supplementary Figures 1-10, Supplementary Tables 1-2, Supplementary Methods and Supplementary References

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