1. Structural Biology and Molecular Biophysics

Structural insights into SETD3-mediated histidine methylation on β-actin

  1. Qiong Guo
  2. Shanhui Liao  Is a corresponding author
  3. Sebastian Kwiatkowski
  4. Weronika Tomaka
  5. Huijuan Yu
  6. Gao Wu
  7. Xiaoming Tu
  8. Jinrong Min
  9. Jakub Drozak  Is a corresponding author
  10. Chao Xu  Is a corresponding author
  1. University of Science and Technology of China, China
  2. University of Warsaw, Poland
  3. University of Toronto, Canada
https://doi.org/10.7554/eLife.43676
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  1. Qiong Guo
  2. Shanhui Liao
  3. Sebastian Kwiatkowski
  4. Weronika Tomaka
  5. Huijuan Yu
  6. Gao Wu
  7. Xiaoming Tu
  8. Jinrong Min
  9. Jakub Drozak
  10. Chao Xu
(2019)
Structural insights into SETD3-mediated histidine methylation on β-actin
eLife 8:e43676.
https://doi.org/10.7554/eLife.43676
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Abstract

SETD3 is a member of the SET (Su(var)3-9, Enhancer of zeste, and Trithorax) domain protein superfamily and plays important roles in hypoxic pulmonary hypertension, muscle differentiation, and carcinogenesis. Previously we identified SETD3 as the actin-specific methyltransferase that methylates the N3 of His73 on β-actin (Kwiatkowski et al. 2018). Here, we present two structures of S-adenosyl-L-homocysteine-bound SETD3 in complex with either an unmodified β-actin peptide or its His-methylated variant. Structural analyses, supported by biochemical experiments and enzyme activity assays, indicate that the recognition and methylation of β-actin by SETD3 are highly sequence specific, and both SETD3 and β-actin adopt pronounced conformational changes upon binding to each other. In conclusion, this study is the first to show a catalytic mechanism of SETD3-mediated histidine methylation on β-actin, which not only throws light on the protein histidine methylation phenomenon, but also facilitates the design of small molecule inhibitors of SETD3.

Data availability

Diffraction data have been deposited in PDB under the accession codes 6ICV and 6ICT

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Author details

  1. Qiong Guo

    School of Life Sciences, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.

  2. Shanhui Liao

    School of Life Sciences, University of Science and Technology of China, Hefei, China
    For correspondence
    ajsod@mail.ustc.edu.cn
    Competing interests
    The authors declare that no competing interests exist.

  3. Sebastian Kwiatkowski

    Department of Metabolic Regulation, Faculty of Biology, University of Warsaw, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4908-1633

  4. Weronika Tomaka

    Department of Metabolic Regulation, Faculty of Biology, University of Warsaw, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.

  5. Huijuan Yu

    School of Life Sciences, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.

  6. Gao Wu

    School of Life Sciences, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.

  7. Xiaoming Tu

    School of Life Sciences, University of Science and Technology of China, Hefei, China
    Competing interests
    The authors declare that no competing interests exist.

  8. Jinrong Min

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.

  9. Jakub Drozak

    Department of Metabolic Regulation, Faculty of Biology, University of Warsaw, Warsaw, Poland
    For correspondence
    jdrozak@biol.uw.edu.pl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3601-3845

  10. Chao Xu

    School of Life Sciences, University of Science and Technology of China, Hefei, China
    For correspondence
    xuchaor@ustc.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0444-7080

Funding

National Natural Science Foundation of China (31570737)

  • Chao Xu

National Natural Science Foundation of China (31500601)

  • Shanhui Liao

National Natural Science Foundation of China (31501093)

  • Huijuan Yu

Narodowe Centrum Nauki (UMO-2017/27/B/NZ1/00161)

  • Jakub Drozak

National Natural Science Foundation of China (31770806)

  • Chao Xu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2019, Guo et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Qiong Guo
  2. Shanhui Liao
  3. Sebastian Kwiatkowski
  4. Weronika Tomaka
  5. Huijuan Yu
  6. Gao Wu
  7. Xiaoming Tu
  8. Jinrong Min
  9. Jakub Drozak
  10. Chao Xu
(2019)
Structural insights into SETD3-mediated histidine methylation on β-actin
eLife 8:e43676.
https://doi.org/10.7554/eLife.43676

Share this article

https://doi.org/10.7554/eLife.43676

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Further reading

    1. Biochemistry and Chemical Biology

    SETD3 protein is the actin-specific histidine N-methyltransferase

    Sebastian Kwiatkowski, Agnieszka K Seliga ... Jakub Drozak
    Research Article

    Protein histidine methylation is a rare post-translational modification of unknown biochemical importance. In vertebrates, only a few methylhistidine-containing proteins have been reported, including β-actin as an essential example. The evolutionary conserved methylation of β-actin H73 is catalyzed by an as yet unknown histidine N-methyltransferase. We report here that the protein SETD3 is the actin-specific histidine N-methyltransferase. In vitro, recombinant rat and human SETD3 methylated β-actin at H73. Knocking-out SETD3 in both human HAP1 cells and in Drosophila melanogaster resulted in the absence of methylation at β-actin H73 in vivo, whereas β-actin from wildtype cells or flies was > 90% methylated. As a consequence, we show that Setd3-deficient HAP1 cells have less cellular F-actin and an increased glycolytic phenotype. In conclusion, by identifying SETD3 as the actin-specific histidine N-methyltransferase, our work pioneers new research into the possible role of this modification in health and disease and questions the substrate specificity of SET-domain-containing enzymes.