Cell Biochemistry and Biophysics

, Volume 63, Issue 3, pp 223–234

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

  • Igor F. Tsigelny
  • Yuriy Sharikov
  • Jerry P. Greenberg
  • Mark A. Miller
  • Valentina L. Kouznetsova
  • Christopher A. Larson
  • Stephen B. Howell
Original Paper

DOI: 10.1007/s12013-012-9358-x

Cite this article as:
Tsigelny, I.F., Sharikov, Y., Greenberg, J.P. et al. Cell Biochem Biophys (2012) 63: 223. doi:10.1007/s12013-012-9358-x

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.

Keywords

CTR1Molecular modelCopperCisplatinTransporter

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Igor F. Tsigelny
    • 1
    • 2
  • Yuriy Sharikov
    • 1
  • Jerry P. Greenberg
    • 2
  • Mark A. Miller
    • 2
  • Valentina L. Kouznetsova
    • 2
    • 3
  • Christopher A. Larson
    • 3
  • Stephen B. Howell
    • 3
  1. 1.Department of NeurosciencesUniversity of California, San DiegoSan DiegoUSA
  2. 2.San Diego Supercomputer CenterUniversity of California, San DiegoSan DiegoUSA
  3. 3.Moores Cancer CenterUniversity of California, San DiegoLa JollaUSA