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Solution structures of the two PBZ domains from human APLF and their interaction with poly(ADP-ribose)

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Abstract

Addition of poly(ADP-ribose) (PAR) is an important post-translational modification in higher eukaryotes. Several DNA repair and checkpoint proteins possess specific PAR-binding zinc-finger (PBZ) modules critical for function. Here, we present solution structures of the two PBZ modules of aprataxin and PNK–like factor (APLF), revealing a novel type of zinc finger. By combining in vivo PAR-binding data with NMR interaction data using PAR fragments, we propose a structural basis for PBZ-PAR recognition.

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Figure 1: Structures of the PBZ modules of APLF.
Figure 2: Structures of APLF PBZ modules in complex with RFA.
Figure 3: Interactions of APLF with PAR and PARP-1 are mediated by PBZ.

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Acknowledgements

We thank A. Murzin, A. Andreeva and C. Rademacher for helpful discussions, G. Smith (AstraZeneca) for the PARP inhibitor KU-0058948, W. Vranken for help with data deposition and C. Oubridge for help with MS. S.E. was funded by a studentship from Boehringer Ingelheim Fonds, C.B. by a fellowship from the Federation of European Biochemical Societies and I.A. by fellowships from Cancer Research UK and the Louis-Jeantet Foundation.

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Author notes

  1. Sebastian Eustermann and Christoph Brockmann: These authors contributed equally to this work.

Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Cambridge, UK

    Sebastian Eustermann, Christoph Brockmann, Ji-Chun Yang, David Loakes & David Neuhaus

  2. Paterson Institute for Cancer Research, University of Manchester, Manchester, UK

    Pawan Vinod Mehrotra & Ivan Ahel

  3. Cancer Research UK, London Research Institute, Clare Hall Laboratories, Hertfordshire, South Mimms, UK

    Stephen C West

Authors
  1. Sebastian Eustermann
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  2. Christoph Brockmann
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  3. Pawan Vinod Mehrotra
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  4. Ji-Chun Yang
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  5. David Loakes
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  6. Stephen C West
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  7. Ivan Ahel
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  8. David Neuhaus
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Contributions

S.E. cloned the construct; S.E., P.V.M. and I.A. designed and performed biochemical experiments; D.L. synthesized the RFA ligand; P.V.M. performed the in vivo binding analyses; S.E., J.-C.Y. and C.B. performed and analyzed NMR experiments; S.E., C.B. and D.N. calculated and analyzed the structures; S.E., I.A., S.C.W. and D.N. wrote the manuscript; D.N. supervised the project.

Corresponding author

Correspondence to David Neuhaus.

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The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Figures 1–11 and Supplementary Tables 1 and 2 (PDF 3773 kb)

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Eustermann, S., Brockmann, C., Mehrotra, P. et al. Solution structures of the two PBZ domains from human APLF and their interaction with poly(ADP-ribose). Nat Struct Mol Biol 17, 241–243 (2010). https://doi.org/10.1038/nsmb.1747

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  • DOI: https://doi.org/10.1038/nsmb.1747

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