Molecular basis for hierarchical histone de-β-hydroxybutyrylation by SIRT3

Xingrun Zhang; Ruili Cao; Jinrong Niu; Shumin Yang; Huida Ma; Shuai Zhao; Haitao Li

doi:10.1038/s41421-019-0103-0

Molecular basis for hierarchical histone de-β-hydroxybutyrylation by SIRT3

Cell Discov. 2019 Jul 9:5:35. doi: 10.1038/s41421-019-0103-0. eCollection 2019.

Authors

Xingrun Zhang¹, Ruili Cao¹, Jinrong Niu¹, Shumin Yang¹, Huida Ma¹, Shuai Zhao¹, Haitao Li¹

Affiliation

¹ MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, 100084 Beijing, China.

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 class-selective histone de-β-hydroxybutyrylase activities with preference for H3 K4, K9, K18, K23, K27, and H4K16, but not for H4 K5, K8, K12, which distinguishes it from the Zn-dependent HDACs. 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 of SIRT3 is due to an entropically unfavorable barrier associated with the glycine-flanking motif that the histone Kbhb resides in. Collectively, we reveal the molecular basis for class-selective histone de-β-hydroxybutyrylation by SIRT3, shedding lights on the function of sirtuins in Kbhb biology through hierarchical deacylation.

Keywords: Histone post-translational modifications; X-ray crystallography.