Insights into the N-terminal Cu(II) and Cu(I) binding sites of the human copper transporter CTR1

Yulia Shenberger, Ortal Marciano, Hugo E. Gottlieb, Sharon Ruthstein

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Copper transporter 1 (CTR1) is the main copper transporter in the eukaryotic system. CTR1 has several important roles: It binds Cu(II) ions that are present in the blood; it reduces those Cu(II) ions to Cu(I); and it subsequently transfers Cu(I) to the cytoplasmic domain, where the ion is delivered to various cellular pathways. Here, we seek to identify CTR1 binding sites for Cu(II) and Cu(I) and to shed light on the Cu(II)-to-Cu(I) reduction process. We focus on the first 14 amino acids of CTR1. This N-terminal segment is rich with histidine and methionine residues, which are known to bind Cu(II) and Cu(I), respectively; thus, this region has been suggested to have an important function in recruiting Cu(II) and reducing it to Cu(I). We utilize electron paramagnetic resonance (EPR) spectroscopy together with nuclear magnetic resonance (NMR) and UV-VIS spectroscopy and alanine substitution to reveal Cu(II) and Cu(I) binding sites in the focal 14-amino-acid segment. We show that H5 and H6 directly coordinate to Cu(II), whereas M7, M9, and M12 are involved in Cu(I) binding. This research is another step on the way to a complete understanding of the cellular copper regulation mechanism in humans.

Original languageEnglish
Pages (from-to)1985-2002
Number of pages18
JournalJournal of Coordination Chemistry
Issue number11-13
StatePublished - 3 Jul 2018

Bibliographical note

Publisher Copyright:
© 2018, © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.


This work was supported by Israel Science Foundation (ISF) [grant number 280/12] and by the European Research Council starting [grant number 745365].

FundersFunder number
European Research Council starting745365
Horizon 2020 Framework Programme754365
Israel Science Foundation280/12


    • CTR1
    • Copper transporter
    • copper binding
    • copper cycle
    • magnetic resonance
    • methionine segments


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