Molecular Basis for Hierarchical Histone De-Β-Hydroxybutyrylation by Sirt3
59 Pages Posted: 16 Aug 2018 Last revised: 4 Sep 2018 Publication Status: Review CompleteMore...
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.
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