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Molecular Basis for Hierarchical Histone De-Β-Hydroxybutyrylation by Sirt3

59 Pages Posted: 16 Aug 2018 Last revised: 4 Sep 2018 Sneak Peek Status: Review Complete

See all articles by Xingrun Zhang

Xingrun Zhang

Tsinghua University - MOE Key Laboratory of Protein Sciences

Ruili Cao

Tsinghua University - MOE Key Laboratory of Protein Sciences

Jinrong Niu

Tsinghua University - MOE Key Laboratory of Protein Sciences

Shumin Yang

Tsinghua University - MOE Key Laboratory of Protein Sciences

Shuai Zhao

Tsinghua University - MOE Key Laboratory of Protein Sciences

Haitao Li

Tsinghua University - MOE Key Laboratory of Protein Sciences

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Abstract

Chemical modifications on histones constitute a key mechanism for gene regulation in chromatin context. Recently, histone lysine β-hydroxybutyrylation (Kbhb) was identified as a new form of histone acylation that connects starvation-responsive metabolism to epigenetic regulation. Sirtuins are a family of NAD+-dependent deacetylases. Through systematic profiling studies, we show that human SIRT3 displays unique class-selective histone de-β-hydroxybutyrylase activities with preferences for H3 K4, K9, K18, K23, K27 and H4K16, but not H4 K5, K8, K12. Structural studies revealed a hydrogen bond-lined hydrophobic pocket favored for the S-form Kbhb recognition and catalysis. β-backbone but not side chain-mediated interactions around Kbhb dominate sequence motif recognition, explaining the broad site-specificity of SIRT3. The observed class-selectivity against sites like H4K8 is due to the intrinsic flexibility of the glycine-flanking motif they reside in. Collectively, we revealed the molecular basis for class-selective histone de-β-hydroxybutyrylation by SIRT3, shedding new lights on the function of sirtuins in Kbhb biology through hierarchical deacylation.

Suggested Citation

Zhang, Xingrun and Cao, Ruili and Niu, Jinrong and Yang, Shumin and Zhao, Shuai and Li, Haitao, Molecular Basis for Hierarchical Histone De-Β-Hydroxybutyrylation by Sirt3. Available at SSRN: https://ssrn.com/abstract=3231848 or http://dx.doi.org/10.2139/ssrn.3231848
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Xingrun Zhang (Contact Author)

Tsinghua University - MOE Key Laboratory of Protein Sciences

Beijing, 100084
China

Ruili Cao

Tsinghua University - MOE Key Laboratory of Protein Sciences

Beijing, 100084
China

Jinrong Niu

Tsinghua University - MOE Key Laboratory of Protein Sciences

Beijing, 100084
China

Shumin Yang

Tsinghua University - MOE Key Laboratory of Protein Sciences

Beijing, 100084
China

Shuai Zhao

Tsinghua University - MOE Key Laboratory of Protein Sciences

Beijing, 100084
China

Haitao Li

Tsinghua University - MOE Key Laboratory of Protein Sciences ( email )

Beijing, 100084
China

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