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Elife. 2019 Feb 20;8. pii: e43676. doi: 10.7554/eLife.43676.

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

Author information

1
Division of Molecular and Cellular Biophysics, Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China.
2
Department of Metabolic Regulation, Faculty of Biology, University of Warsaw, Warsaw, Poland.
3
Structural Genomics Consortium, University of Toronto, Toronto, Canada.
4
Department of Physiology, University of Toronto, Toronto, Canada.
#
Contributed equally

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 that 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.

KEYWORDS:

E. coli; N3-methylhistidine; SET domain; X-ray crystallography; molecular biophysics; post translational modifications; structural biology; β-actin

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