| Structural highlights
Disease
ATP7B_HUMAN Defects in ATP7B are the cause of Wilson disease (WD) [MIM:277900. WD is an autosomal recessive disorder of copper metabolism in which copper cannot be incorporated into ceruloplasmin in liver, and cannot be excreted from the liver into the bile. Copper accumulates in the liver and subsequently in the brain and kidney. The disease is characterized by neurologic manifestations and signs of cirrhosis.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51]
Function
ATP7B_HUMAN Involved in the export of copper out of the cells, such as the efflux of hepatic copper into the bile.
Publication Abstract from PubMed
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.
Tetrathiomolybdate induces dimerization of the metal-binding domain of ATPase and inhibits platination of the protein.,Fang T, Chen W, Sheng Y, Yuan S, Tang Q, Li G, Huang G, Su J, Zhang X, Zang J, Liu Y Nat Commun. 2019 Jan 14;10(1):186. doi: 10.1038/s41467-018-08102-z. PMID:30643139[52]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Kusuda Y, Hamaguchi K, Mori T, Shin R, Seike M, Sakata T. Novel mutations of the ATP7B gene in Japanese patients with Wilson disease. J Hum Genet. 2000;45(2):86-91. PMID:10721669 doi:10.1007/s100380050017
- ↑ Lee CC, Wu JY, Tsai FJ, Kodama H, Abe T, Yang CF, Tsai CH. Molecular analysis of Wilson disease in Taiwan: identification of one novel mutation and evidence of haplotype-mutation association. J Hum Genet. 2000;45(5):275-9. PMID:11043508 doi:10.1007/s100380070015
- ↑ Genschel J, Czlonkowska A, Sommer G, Buettner C, Bochow B, Lochs H, Schmidt H. Three novel mutations (P760L, L1305P, Q1351Stop) causing Wilson disease. Hum Mutat. 2001 Feb;17(2):156. PMID:11180609 doi:<156::AID-HUMU18>3.0.CO;2-0 10.1002/1098-1004(200102)17:2<156::AID-HUMU18>3.0.CO;2-0
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- ↑ Ohya K, Abo W, Tamaki H, Sugawara C, Endo T, Nomachi S, Fukushi M, Kinebuchi M, Matsuura A. Presymptomatic diagnosis of Wilson disease associated with a novel mutation of the ATP7B gene. Eur J Pediatr. 2002 Feb;161(2):124-6. PMID:11954751
- ↑ Yoo HW. Identification of novel mutations and the three most common mutations in the human ATP7B gene of Korean patients with Wilson disease. Genet Med. 2002 Nov-Dec;4(6 Suppl):43S-48S. PMID:12544487 doi:10.109700125817-200211001-00009
- ↑ Loudianos G, Lovicu M, Dessi V, Tzetis M, Kanavakis E, Zancan L, Zelante L, Galvez-Galvez C, Cao A. Abnormal mRNA splicing resulting from consensus sequence splicing mutations of ATP7B. Hum Mutat. 2002 Oct;20(4):260-6. PMID:12325021 doi:10.1002/humu.10121
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- ↑ Majumdar R, Al-Jumah M, Zaidan R. A rare homozygous missense mutation in ATP7B exon 19 in a case of Wilson disease. Eur Neurol. 2004;51(1):52-4. Epub 2003 Nov 21. PMID:14639035 doi:10.1159/000075092
- ↑ Deguti MM, Genschel J, Cancado EL, Barbosa ER, Bochow B, Mucenic M, Porta G, Lochs H, Carrilho FJ, Schmidt HH. Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat. 2004 Apr;23(4):398. PMID:15024742 doi:10.1002/humu.9227
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- ↑ Dedoussis GV, Genschel J, Sialvera TE, Bochow B, Manolaki N, Manios Y, Tsafantakis E, Schmidt H. Wilson disease: high prevalence in a mountainous area of Crete. Ann Hum Genet. 2005 May;69(Pt 3):268-74. PMID:15845031 doi:10.1046/j.1529-8817.2005.00171.x
- ↑ Kumar S, Thapa BR, Kaur G, Prasad R. Identification and molecular characterization of 18 novel mutations in the ATP7B gene from Indian Wilson disease patients: genotype. Clin Genet. 2005 May;67(5):443-5. PMID:15811015 doi:10.1111/j.1399-0004.2005.00440.x
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- ↑ Gromadzka G, Schmidt HH, Genschel J, Bochow B, Rodo M, Tarnacka B, Litwin T, Chabik G, Czlonkowska A. Frameshift and nonsense mutations in the gene for ATPase7B are associated with severe impairment of copper metabolism and with an early clinical manifestation of Wilson's disease. Clin Genet. 2005 Dec;68(6):524-32. PMID:16283883 doi:10.1111/j.1399-0004.2005.00528.x
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- ↑ Fang T, Chen W, Sheng Y, Yuan S, Tang Q, Li G, Huang G, Su J, Zhang X, Zang J, Liu Y. Tetrathiomolybdate induces dimerization of the metal-binding domain of ATPase and inhibits platination of the protein. Nat Commun. 2019 Jan 14;10(1):186. doi: 10.1038/s41467-018-08102-z. PMID:30643139 doi:http://dx.doi.org/10.1038/s41467-018-08102-z
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