Molecular basis for hierarchical histone de-beta-hydroxybutmlation by SIRT3
Molecular basis for hierarchical histone de-beta-hydroxybutmlation by SIRT3
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SIRT3 分层组蛋白去β-羟基丁化的分子基础
DOI：
10.1038/s41421-019-0103-0
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发表时间：
--
期刊：
影响因子：
33.5
通讯作者：
Li Haitao
中科院分区：
文献类型：
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作者：
Zhang Xingrun;Cao Ruili;Niu Jinrong;Yang Shumin;Ma Huida;Zhao Shuai;Li Haitao
组蛋白的化学修饰是染色质环境中基因调控的关键机制。最近，组蛋白赖氨酸β-羟丁酰化(KBHb)被确定为一种新的组蛋白酰化形式，它将饥饿反应代谢与表观遗传调节联系起来。Sirtuins是一类依赖NAD+的脱乙酰酶家族。通过系统的图谱研究，我们发现人类SIRT3表现出类选择性的组蛋白去β-羟丁酰基酶活性，对H3K4，K9，K18，K23，K27和H4K16有偏好，而对H4K5，K8，K12没有选择性，这是它与依赖锌的HDAC的区别。结构研究表明，氢键衬里的疏水口袋有利于Sform KbHb的识别和催化。β主干而不是KBHb周围的侧链介导的相互作用主导着序列基序的识别，解释了SIRT3广泛的位点特异性。观察到的SIRT3的类选择性是由于与组蛋白KBHb所在的甘氨酸侧翼基序有关的一个熵不利的障碍。我们共同揭示了SIRT3对组蛋白去β-羟丁酰化的类选择性的分子基础，揭示了sirtuins在KBHb生物学中通过分级脱酰作用的功能。
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 starvationresponsive 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 Sform 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.