Structural insights into SETD3-mediated histidine methylation on β-actin
Qiong Guo,
Shanhui Liao,
Sebastian Kwiatkowski,
Weronika Tomaka,
Huijuan Yu,
Gao Wu,
Xiaoming Tu,
Jinrong Min,
Jakub Drozak,
Chao Xu
Affiliations
Qiong Guo
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
Shanhui Liao
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
Weronika Tomaka
Department of Metabolic Regulation, Faculty of Biology, University of Warsaw, Warsaw, Poland
Huijuan Yu
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
Gao Wu
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
Xiaoming Tu
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
Jinrong Min
Structural Genomics Consortium, University of Toronto, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada
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
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.
