Biochemistry, Department of



Yan Guo

Date of this Version



The Journal of Biological Chemistry, Vol. 279, No. 17, Issue of April 23, pp. 17428–17433, 2004


Copyright 2004 by The American Society for Biochemistry and Molecular Biology, Inc.


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.