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

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...

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Autores principales: Guo, Qiong, Liao, Shanhui, Kwiatkowski, Sebastian, Tomaka, Weronika, Yu, Huijuan, Wu, Gao, Tu, Xiaoming, Min, Jinrong, Drozak, Jakub, Xu, Chao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400499/
https://www.ncbi.nlm.nih.gov/pubmed/30785395
http://dx.doi.org/10.7554/eLife.43676
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author Guo, Qiong
Liao, Shanhui
Kwiatkowski, Sebastian
Tomaka, Weronika
Yu, Huijuan
Wu, Gao
Tu, Xiaoming
Min, Jinrong
Drozak, Jakub
Xu, Chao
author_facet Guo, Qiong
Liao, Shanhui
Kwiatkowski, Sebastian
Tomaka, Weronika
Yu, Huijuan
Wu, Gao
Tu, Xiaoming
Min, Jinrong
Drozak, Jakub
Xu, Chao
author_sort Guo, Qiong
collection PubMed
description 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.
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spelling pubmed-64004992019-03-06 Structural insights into SETD3-mediated histidine methylation on β-actin Guo, Qiong Liao, Shanhui Kwiatkowski, Sebastian Tomaka, Weronika Yu, Huijuan Wu, Gao Tu, Xiaoming Min, Jinrong Drozak, Jakub Xu, Chao eLife Structural Biology and Molecular Biophysics 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. eLife Sciences Publications, Ltd 2019-02-20 /pmc/articles/PMC6400499/ /pubmed/30785395 http://dx.doi.org/10.7554/eLife.43676 Text en © 2019, Guo et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Structural Biology and Molecular Biophysics
Guo, Qiong
Liao, Shanhui
Kwiatkowski, Sebastian
Tomaka, Weronika
Yu, Huijuan
Wu, Gao
Tu, Xiaoming
Min, Jinrong
Drozak, Jakub
Xu, Chao
Structural insights into SETD3-mediated histidine methylation on β-actin
title Structural insights into SETD3-mediated histidine methylation on β-actin
title_full Structural insights into SETD3-mediated histidine methylation on β-actin
title_fullStr Structural insights into SETD3-mediated histidine methylation on β-actin
title_full_unstemmed Structural insights into SETD3-mediated histidine methylation on β-actin
title_short Structural insights into SETD3-mediated histidine methylation on β-actin
title_sort structural insights into setd3-mediated histidine methylation on β-actin
topic Structural Biology and Molecular Biophysics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400499/
https://www.ncbi.nlm.nih.gov/pubmed/30785395
http://dx.doi.org/10.7554/eLife.43676
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