Biochemistry, Department of
Identification of Methionine-rich Clusters That Regulate Copper-stimulated Endocytosis of the Human Ctr1 Copper Transporter
Date of this Version
The Journal of Biological Chemistry, Vol. 279, No. 17, Issue of April 23, pp. 17428–17433, 2004
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.
Copyright 2004 by The American Society for Biochemistry and Molecular Biology, Inc.