A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol.
A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol.
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DOI：
10.1038/nature14028
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发表时间：
2015-03-19
期刊：
影响因子：
64.8
通讯作者：
Schimmel, Paul
中科院分区：
文献类型：
--
作者：
Sajish, Mathew;Schimmel, Paul
据报道，白藜芦醇（Resveratrol， RSV）通过启动诱导生存基因的应激反应，延长寿命并提供心脏神经保护、抗糖尿病和抗癌作用。由于人酪氨酸基tRNA合成酶（TyrRS）在应激条件下易位到细胞核，我们考虑RSV的酪氨酸样酚环可能适合活性位点口袋，从而发挥核作用。本文提出了结合TyrRS活性位点的RSV的2.1Å共晶结构。RSV使催化活性无效，并将TyrRS重定向到核功能，刺激PARP-1依赖NAD+的自聚adp核糖基化。下游关键应激信号通路的激活与TyrRS-PARP-1-NAD+协同作用有因果关系。这种合作也在小鼠中得到证实，并且在体内被rsv取代的酪氨酸腺苷酸类似物特异性阻断。与选择性剪接事件导致的tRNA合成酶催化空位点不同，非剪接的TyrRS催化空位点揭示了RSV生理机制的一个新的PARP-1和NAD+依赖维度。
Resveratrol (RSV) is reported to extend life span and provide cardio-neuro-protective, anti-diabetic, and anti-cancer effects by initiating a stress response that induces survival genes. Because human tyrosyl tRNA synthetase (TyrRS) translocates to the nucleus under stress conditions, we considered the possibility that the tyrosine-like phenolic ring of RSV might fit into the active site pocket to effect a nuclear role. Here we present a 2.1Å co-crystal structure of RSV bound to the active site of TyrRS. RSV nullified the catalytic activity and redirected TyrRS to a nuclear function, stimulating NAD+-dependent auto-poly-ADP-ribosylation of PARP-1. Downstream activation of key stress signaling pathways were causally connected to TyrRS-PARP-1-NAD+ collaboration. This collaboration was also demonstrated in the mouse, and was specifically blocked in vivo by a RSV-displacing tyrosyl adenylate analog. In contrast to functionally diverse tRNA synthetase catalytic nulls created by alternative splicing events that ablate active sites, here a non-spliced TyrRS catalytic null reveals a new PARP-1- and NAD+-dependent dimension to the physiological mechanism of RSV.
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