Send to

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

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

Author information

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.
Department of Metabolic Regulation, Faculty of Biology, University of Warsaw, Warsaw, Poland.
Structural Genomics Consortium, University of Toronto, Toronto, Canada.
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.


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

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center