Tetrathiomolybdate induces dimerization of the metal-binding domain of ATPase and inhibits platination of the protein

Tiantian Fang, Wanbiao Chen, Yaping Sheng, Siming Yuan, Qiaowei Tang, Gongyu Li, Guangming Huang, Jihu Su, Xuan Zhang (), Jianye Zang () and Yangzhong Liu ()
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Tiantian Fang: CAS Key Laboratory of Soft Matter Chemistry, Department of Chemistry, University of Science and Technology of China
Wanbiao Chen: Hefei National Laboratory for Physical Sciences at Microscale CAS Center for Excellence in Biomacromolecules, Collaborative Innovation Center of Chemistry for Life Sciences, and School of Life Sciences, University of Science and Technology of China
Yaping Sheng: CAS Key Laboratory of Soft Matter Chemistry, Department of Chemistry, University of Science and Technology of China
Siming Yuan: CAS Key Laboratory of Soft Matter Chemistry, Department of Chemistry, University of Science and Technology of China
Qiaowei Tang: University of Science and Technology of China
Gongyu Li: CAS Key Laboratory of Soft Matter Chemistry, Department of Chemistry, University of Science and Technology of China
Guangming Huang: CAS Key Laboratory of Soft Matter Chemistry, Department of Chemistry, University of Science and Technology of China
Jihu Su: University of Science and Technology of China
Xuan Zhang: Hefei National Laboratory for Physical Sciences at Microscale CAS Center for Excellence in Biomacromolecules, Collaborative Innovation Center of Chemistry for Life Sciences, and School of Life Sciences, University of Science and Technology of China
Jianye Zang: Hefei National Laboratory for Physical Sciences at Microscale CAS Center for Excellence in Biomacromolecules, Collaborative Innovation Center of Chemistry for Life Sciences, and School of Life Sciences, University of Science and Technology of China
Yangzhong Liu: CAS Key Laboratory of Soft Matter Chemistry, Department of Chemistry, University of Science and Technology of China

Nature Communications, 2019, vol. 10, issue 1, 1-8

Abstract: Abstract Tetrathiomolybdate (TM) is used in the clinic for the treatment of Wilson’s disease by targeting the cellular copper efflux protein ATP7B (WLN). Interestingly, both TM and WLN are associated with the efficacy of cisplatin, a widely used anticancer drug. Herein, we show that TM induces dimerization of the metal-binding domain of ATP7B (WLN4) through a unique sulfur-bridged Mo2S6O2 cluster. TM expels copper ions from Cu-WLN4 and forms a copper-free dimer. The binding of Mo to cysteine residues of WLN4 inhibits platination of the protein. Reaction with multi-domain proteins indicates that TM can also connect two domains in the same molecule, forming Mo-bridged intramolecular crosslinks. These results provide structural and chemical insight into the mechanism of action of TM against ATPase, and reveal the molecular mechanism by which TM attenuates the cisplatin resistance mediated by copper efflux proteins.

Date: 2019
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DOI: 10.1038/s41467-018-08102-z

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