Ctr1 Intracellular Loop Is Involved in the Copper Transfer Mechanism to the Atox1 Metallochaperone

Ariel R. Levy, Matan Nissim, Netanel Mendelman, Jordan Chill, Sharon Ruthstein

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Understanding the human copper cycle is essential to understand the role of metals in promoting neurological diseases and disorders. One of the cycles controlling the cellular concentration and distribution of copper involves the copper transporter, Ctr1; the metallochaperone, Atox1; and the ATP7B transporter. It has been shown that the C-terminus of Ctr1, specifically the last three amino acids, HCH, is involved in both copper coordination and the transfer mechanism to Atox1. In contrast, the role of the intracellular loop of Ctr1, which is an additional intracellular segment of Ctr1, in facilitating the copper transfer mechanism has not been investigated yet. Here, we combine various biophysical methods to explore the interaction between this Ctr1 segment and metallochaperone Atox1 and clearly demonstrate that the Ctr1 intracellular loop (1) can coordinate Cu(I) via interactions with the side chains of one histidine and two methionine residues and (2) closely interacts with the Atox1 metallochaperone. Our findings are another important step in elucidating the mechanistic details of the eukaryotic copper cycle.

Original languageEnglish
Pages (from-to)12334-12345
Number of pages12
JournalJournal of Physical Chemistry B
Issue number48
StatePublished - 8 Dec 2016

Bibliographical note

Funding Information:
This study was supported by the Israel Science Foundation, grant no. 280/12. The Elexsys E580 Bruker EPR spectrometer was partially supported by the Israel Science Foundation, grant no. 564/12. The 700 MHz spectrometer system was partially funded by a generous donation from Fundacion Adar. We are thankful to Ortal Marciano for her assistance with the SDS-PAGE gel experiments.

Publisher Copyright:
© 2016 American Chemical Society.


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