An alternative conformation of human TrpRS suggests a role of zinc in activating non-enzymatic function

作者：Xu, Xiaoling^*; Zhou, Huihao; Zhou, Quansheng; Hong, Fei; My-Nuong Vo; Niu, Wanqiang; Wang, Zhiguo; Xiong, Xiaolin; Nakamura, Kanaha; Wakasugi, Keisuke; Schimmel, Paul; Yang, Xiang-Lei^*

来源：RNA Biology, 2018, 15(4-5): 649-658.

DOI：10.1080/15476286.2017.1377868

• Anti-angiogenesis
• crystal structure
• H130R T2-TrpRS
• Tryptophanyl-tRNA synthetase
• VE-cadherin

Tryptophanyl-tRNA synthetase (TrpRS) in vertebrates contains a N-terminal extension in front of the catalytic core. Proteolytic removal of the N-terminal 93 amino acids gives rise to T2-TrpRS, which has potent anti-angiogenic activity mediated through its extracellular interaction with VE-cadherin. Zinc has been shown to have anti-angiogenic effects and can bind to human TrpRS. However, the connection between zinc and the anti-angiogenic function of TrpRS has not been explored. Here we report that zinc binding can induce structural relaxation in human TrpRS to facilitate the proteolytic generation of a T2-TrpRS-like fragment. The zinc-binding site is likely to be contained within T2-TrpRS, and the zinc-bound conformation of T2-TrpRS is mimicked by mutation H130R. We determined the crystal structure of H130R T2-TrpRS at 2.8 angstrom resolution, which reveals drastically different conformation from that of wild-type (WT) T2-TrpRS. The conformational change creates larger binding surfaces for VE-cadherin as suggested by molecular dynamic simulations. Surface plasmon resonance analysis indicates more than 50-fold increase in binding affinity of H130R T2-TrpRS for VE-cadherin, compared to WT T2-TrpRS. The enhanced interaction is also confirmed by a cell-based binding analysis. These results suggest that zinc plays an important role in activating TrpRS for angiogenesis regulation.

• 出版日期2018
• 单位杭州师范大学