Sajish Mathew, Schimmel Paul
The Skaggs Institute for Chemical Biology, The Scripps Laboratories for tRNA Synthetase Research, Department of Molecular and Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
1] The Skaggs Institute for Chemical Biology, The Scripps Laboratories for tRNA Synthetase Research, Department of Molecular and Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA [2] The Scripps Florida Research Institute, 130 Scripps Way, Jupiter, Florida 33458, USA.
Nature. 2015 Mar 19;519(7543):370-3. doi: 10.1038/nature14028. Epub 2014 Dec 22.
Resveratrol is reported to extend lifespan and provide cardio-neuro-protective, anti-diabetic, and anti-cancer effects by initiating a stress response that induces survival genes. Because human tyrosyl transfer-RNA (tRNA) synthetase (TyrRS) translocates to the nucleus under stress conditions, we considered the possibility that the tyrosine-like phenolic ring of resveratrol might fit into the active site pocket to effect a nuclear role. Here we present a 2.1 Å co-crystal structure of resveratrol bound to the active site of TyrRS. Resveratrol nullifies the catalytic activity and redirects TyrRS to a nuclear function, stimulating NAD(+)-dependent auto-poly-ADP-ribosylation of poly(ADP-ribose) polymerase 1 (PARP1). Downstream activation of key stress signalling pathways are causally connected to TyrRS-PARP1-NAD(+) collaboration. This collaboration is also demonstrated in the mouse, and is specifically blocked in vivo by a resveratrol-displacing tyrosyl adenylate analogue. 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 PARP1- and NAD(+)-dependent dimension to the physiological mechanism of resveratrol.
据报道，白藜芦醇可通过引发诱导生存基因的应激反应来延长寿命，并提供心脏神经保护、抗糖尿病和抗癌作用。由于人类酪氨酰转移RNA（tRNA）合成酶（TyrRS）在应激条件下会转移至细胞核，我们推测白藜芦醇中类似酪氨酸的酚环可能会嵌入活性位点口袋以发挥核作用。在此，我们展示了白藜芦醇与TyrRS活性位点结合的2.1埃共晶体结构。白藜芦醇使催化活性失效，并将TyrRS重定向至核功能，刺激聚（ADP - 核糖）聚合酶1（PARP1）的NAD⁺依赖性自动多聚ADP核糖基化。关键应激信号通路的下游激活与TyrRS - PARP1 - NAD⁺协作存在因果关联。这种协作在小鼠中也得到了证实，并且在体内被一种取代白藜芦醇的酪氨酰腺苷酸类似物特异性阻断。与通过切除活性位点的可变剪接事件产生的功能多样的tRNA合成酶催化无效突变体不同，此处一个未剪接的TyrRS催化无效突变体揭示了白藜芦醇生理机制中一个新的PARP1和NAD⁺依赖性维度。
