Structural insights into SETD3-mediated histidine methylation on β-actin
- Elife. 2019 Feb 20;8:e43676. doi: 10.7554/eLife.43676.
- 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.
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.