Identification of Methionine-rich Clusters That Regulate Copper-stimulated Endocytosis of the Human Ctr1 Copper Transporter

Yan Guo, Kathryn Smith, Jaekwon Lee, Dennis J. Thiele, Michael J. Petris

Research output: Contribution to journalArticlepeer-review

142 Scopus citations


Copper uptake and subsequent delivery to copper-dependent enzymes are essential for many cellular processes. However, the intracellular levels of this nutrient must be controlled because of its potential toxicity. The hCtr1 protein functions in high affinity copper uptake at the plasma membrane of human cells. Recent studies have shown that elevated copper stimulates the endocytosis and degradation of the hCtr1 protein, and this response is likely an important homeostatic mechanism that prevents the overaccumulation of copper. The domains of hCtr1 involved in copper-stimulated endocytosis and degradation are unknown. In this study we examined the importance of potential copper-binding sequences in the extracellular domain and a conserved transmembrane 150MXXXM154 motif for copper-stimulated endocytosis and degradation of hCtr1. The endocytic response of hCtr1 to low copper concentrations required an amino-terminal methionine cluster ( 40MMMMPM45) closest to the transmembrane region. However, this cluster was not required for the endocytic response to higher copper levels, suggesting this motif may function as a high affinity copper-sensing domain. Moreover, the transmembrane 150MXXXM154 motif was absolutely required for copper-stimulated endocytosis and degradation of hCtr1 even under high copper concentrations. Together with previous studies demonstrating a role for these motifs in high affinity copper transport activity, our findings suggest common biochemical mechanisms regulate both transport and trafficking functions of hCtr1.

Original languageEnglish (US)
Pages (from-to)17428-17433
Number of pages6
JournalJournal of Biological Chemistry
Issue number17
StatePublished - Apr 23 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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