Structural insights into SETD3-mediated histidine methylation on β-actin
- University of Science and Technology of China, China
- University of Warsaw, Poland
- University of Toronto, Canada
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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Structure of SETD3 bound to SAH and methylated actinProtein Data Bank, 6ICT.
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Structure of SETD3 bound to SAH and unmodified actinProtein Data Bank, 6ICV.
Article and author information
Author details
Sebastian Kwiatkowski
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
- Philip A Cole, Harvard Medical School, United States
Version history
- Received: November 19, 2018
- Accepted: February 19, 2019
- Accepted Manuscript published: February 20, 2019 (version 1)
- Version of Record published: March 5, 2019 (version 2)
- 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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Structural insights into SETD3-mediated histidine methylation on β-actin
eLife 8:e43676.
https://doi.org/10.7554/eLife.43676
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