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

Tiantian Fang,Jianye Zang,Guangming Huang,Qiaowei Tang,Yangzhong Liu,Wanbiao Chen,Jihu Su,Gongyu Li,Yaping Sheng,Xuan Zhang,Siming Yuan

doi:10.1038/s41467-018-08102-z

Tiantian Fang, Jianye Zang + Show 9 more

Open Access

https://doi.org/10.1038/s41467-018-08102-z

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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.

Highlights

Tetrathiomolybdate (TM) is used in the clinic for the treatment of Wilson’s disease by targeting the cellular copper efflux protein ATP7B (WLN)
These two proteins are known as Menkes (MNK) and Wilson (WLN) disease proteins, since dysfunction of ATP7A and ATP7B leads to these diseases, respectively
The reaction of TM with Cu-WLN4 generated a yellow complex, and the product was purified by size-exclusion chromatography (SEC) (Supplementary Fig. 3a)

Summary

Introduction

Tetrathiomolybdate (TM) is used in the clinic for the treatment of Wilson’s disease by targeting the cellular copper efflux protein ATP7B (WLN) Both TM and WLN are associated with the efficacy of cisplatin, a widely used anticancer drug. Reaction with multi-domain proteins indicates that TM can 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. These two proteins are known as Menkes (MNK) and Wilson (WLN) disease proteins, since dysfunction of ATP7A and ATP7B leads to these diseases, respectively These Cu-ATPases are associated with resistance to cisplatin, one of the most widely used anticancer drugs in the clinic[2,3]. Further studies confirm that the formation of this protein dimer inhibits the reaction of cisplatin, which explains how TM reduces ATPase-related cisplatin resistance

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