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Structural insights into the human GW182-PABC interaction in microRNA-mediated deadenylation

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Abstract

GW182-family proteins are essential for microRNA-mediated translational repression and deadenylation in animal cells. Here we show that a conserved motif in the human GW182 paralog TNRC6C interacts with the C-terminal domain of polyadenylate binding protein 1 (PABC) and present the crystal structure of the complex. Mutations at the complex interface impair mRNA deadenylation in mammalian cell extracts, suggesting that the GW182-PABC interaction contributes to microRNA-mediated gene silencing.

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Figure 1: The DUF domain of TNRC6C interacts with the C-terminal domain of PABPC1.
Figure 2: Disruption of the TNRC6C–PABC interaction interferes with mRNA deadenylation in vitro.

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Acknowledgements

We thank D. King (Howard Hughes Medical Institute Mass Spectrometry Laboratory, Univ. California Berkeley) for peptide synthesis and mass spectrometry, and C. Ralston and J. Holton (Beamlines 8.2.1 and 8.3.1, Advanced Light Source, Lawrence Berkeley National Laboratory) for assistance with X-ray data collection. We are indebted to W. Filipowicz for discussions and to members of the Doudna laboratory for critical reading of the manuscript. M.J. is supported by a Human Frontiers Science Program fellowship. M.R.F. is supported by a Terry Fox Foundation fellowship from the Canadian Cancer Society. This work was funded in part by a Canadian Institutes of Health Research grant to N.S. N.S. is an International Scholar of the Howard Hughes Medical Institute. J.A.D. is a Howard Hughes Medical Institute Investigator.

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Authors and Affiliations

  1. Department of Molecular and Cell Biology, University of California, Berkeley, California, USA

    Martin Jinek, Scott M Coyle & Jennifer A Doudna

  2. Department of Biochemistry, McGill University, Montreal, Quebec, Canada

    Marc R Fabian & Nahum Sonenberg

  3. Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada

    Marc R Fabian & Nahum Sonenberg

  4. Howard Hughes Medical Institute, University of California, Berkeley, California, USA

    Scott M Coyle & Jennifer A Doudna

  5. Department of Chemistry, University of California, Berkeley, California, USA

    Jennifer A Doudna

  6. Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA

    Jennifer A Doudna

Authors
  1. Martin Jinek
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  2. Marc R Fabian
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  3. Scott M Coyle
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  4. Nahum Sonenberg
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  5. Jennifer A Doudna
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Contributions

M.J., M.R.F., N.S. and J.A.D. designed experiments. M.J. performed binding assays, crystallized the TNRC6C–PABC complex and determined its structure. M.R.F. performed in vitro deadenylation assays. S.M.C. assisted with X-ray data collection and structure determination. M.J. and J.A.D. wrote the manuscript.

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Correspondence to Jennifer A Doudna.

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The authors declare no competing financial interests.

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Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Table 1 and Supplementary Methods (PDF 3357 kb)

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Jinek, M., Fabian, M., Coyle, S. et al. Structural insights into the human GW182-PABC interaction in microRNA-mediated deadenylation. Nat Struct Mol Biol 17, 238–240 (2010). https://doi.org/10.1038/nsmb.1768

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