| 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
The P-type ATPase ATP7B exports cytosolic copper and plays an essential role in the regulation of cellular copper homeostasis. Mutants of ATP7B cause Wilson disease (WD), an autosomal recessive disorder of copper metabolism. Here, we present cryoelectron microscopy (cryo-EM) structures of human ATP7B in the E1 state in the apo, the putative copper-bound, and the putative cisplatin-bound forms. In ATP7B, the N-terminal sixth metal-binding domain (MBD6) binds at the cytosolic copper entry site of the transmembrane domain (TMD), facilitating the delivery of copper from the MBD6 to the TMD. The sulfur-containing residues in the TMD of ATP7B mark the copper transport pathway. By comparing structures of the E1 state human ATP7B and E2-P(i) state frog ATP7B, we propose the ATP-driving copper transport model of ATP7B. These structures not only advance our understanding of the mechanisms of ATP7B-mediated copper export but can also guide the development of therapeutics for the treatment of WD.
Structures of the human Wilson disease copper transporter ATP7B.,Yang GM, Xu L, Wang RM, Tao X, Zheng ZW, Chang S, Ma D, Zhao C, Dong Y, Wu S, Guo J, Wu ZY Cell Rep. 2023 May 30;42(5):112417. doi: 10.1016/j.celrep.2023.112417. Epub 2023 , Apr 18. PMID:37074913[52]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ 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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- ↑ 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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- ↑ Yang GM, Xu L, Wang RM, Tao X, Zheng ZW, Chang S, Ma D, Zhao C, Dong Y, Wu S, Guo J, Wu ZY. Structures of the human Wilson disease copper transporter ATP7B. Cell Rep. 2023 Apr 18;42(5):112417. PMID:37074913 doi:10.1016/j.celrep.2023.112417
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