期刊
JOURNAL OF INORGANIC BIOCHEMISTRY
卷 110, 期 -, 页码 8-17出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2012.02.016
关键词
ATP7A; ATP7B; Metal binding sequences; Cisplatin; Platinum containing drugs
资金
- National Institutes of Health [CA152185, CA095298]
- Department of Defense [W81XWH-08-1-0135]
- [P30 NS047101]
- [P30 CA23100]
The copper (Cu) exporter ATP7B mediates resistance to cisplatin (cDDP) but details of the mechanism are unknown. We explored the role of the CXXC motifs in the metal binding domains (MBDs) of ATP7B by investigating binding of cDDP to the sixth metal binding domain (MBD6) or a variant in which the CXXC motif was converted to SXXS. Platinum measurement showed that cDDP bound to wild type MBD6 but not to the SXXS variant. Wild type ATP7B rendered ovarian 2008 cells resistant to cDDP. In 2008 and in HEK293T cells, wild type ATP7B trafficked from TGN to peripheral locations in response to Cu or cDDP. A variant in which the CXXC motifs in all 6 MBDs were converted to SXXS localized correctly to the TGN but failed to traffic when exposed to either Cu or cDDP. Deletion of either the first 5 MBDs or all 6 MBDs resulted in failure to localize to the TGN. Neither the SXXS variant nor the deletion variant was able to mediate resistance to cDDP. We conclude that cDDP binds to the CXXC motifs of ATP7B and that this interaction is essential to the trafficking of ATP7B and to its ability to mediate resistance to cDDP. (C) 2012 Elsevier Inc. All rights reserved.
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