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An All-Atom Model of the Structure of Human Copper Transporter 1

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Abstract

Human copper transporter 1 (hCTR1) is the major high affinity copper influx transporter in mammalian cells that also mediates uptake of the cancer chemotherapeutic agent cisplatin. A low resolution structure of hCTR1 determined by cryoelectron microscopy was recently published. Several protein structure simulation techniques were used to create an all-atom model of this important transporter using the low resolution structure as a starting point. The all-atom model provides new insights into the roles of specific residues of the N-terminal extracellular domain, the intracellular loop, and C-terminal region in metal ion transport. In particular, the model demonstrates that the central region of the pore contains four sets of methionine triads in the intramembranous region. The structure confirms that two triads of methionine residues delineate the intramembranous region of the transporter, and further identifies two additional methionine triads that are located in the extracellular N-terminal part of the transporter. Together, the four triads create a structure that promotes stepwise transport of metal ions into and then through the intramembranous channel of the transporter via transient thioether bonds to methionine residues. Putative copper-binding sites in the hCTR1 trimer were identified by a program developed by us for prediction of metal-binding sites. These sites correspond well with the known effects of mutations on the ability of the protein to transport copper and cisplatin.

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Acknowledgments

This work was supported by grants CA152185 and CA095298 from the National Institutes of Health, grant W81XWH-08-1-0135 from the Department of Defense, and a grant from the Clayton Medical Research Foundation. Additional support for core laboratories was from grants P30 NS047101 for the UCSD Neuroscience Microscopy Shared Facility and the UCSD Cancer Center Specialized Support grant P30 CA23100. We would like to thank Dr. Vincenz Unger for helpful discussions, and Dr. Ben-Tal for sharing the results of his simulation studies.

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Authors and Affiliations

  1. Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, San Diego, CA, 92093-0505, USA

    Igor F. Tsigelny & Yuriy Sharikov

  2. San Diego Supercomputer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, San Diego, CA, 92093-0505, USA

    Igor F. Tsigelny, Jerry P. Greenberg, Mark A. Miller & Valentina L. Kouznetsova

  3. Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA, 92093-0819, USA

    Valentina L. Kouznetsova, Christopher A. Larson & Stephen B. Howell

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  1. Igor F. Tsigelny
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Correspondence to Igor F. Tsigelny.

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Tsigelny, I.F., Sharikov, Y., Greenberg, J.P. et al. An All-Atom Model of the Structure of Human Copper Transporter 1. Cell Biochem Biophys 63, 223–234 (2012). https://doi.org/10.1007/s12013-012-9358-x

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