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

The following data sets were generated

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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.

Reviewing Editor

  1. Philip A Cole, Harvard Medical School, United States

Version history

  1. Received: November 19, 2018
  2. Accepted: February 19, 2019
  3. Accepted Manuscript published: February 20, 2019 (version 1)
  4. Version of Record published: March 5, 2019 (version 2)
  5. Version of Record updated: April 30, 2019 (version 3)

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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    SETD3 protein is the actin-specific histidine N-methyltransferase

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