A Copper-regulated Transporter Required for Copper Acquisition, Pigmentation, and Specific Stages of Development in Drosophila melanogaster

Abstract

The trace element copper is required for normal growth and development, serving as an essential catalytic co-factor for enzymes involved in energy generation, oxidative stress protection, neuropeptide maturation, and other fundamental processes. In yeast and mammals copper acquisition occurs through the action of the Ctr1 family of high affinity copper transporters. Here we describe studies using Drosophila melanogaster to investigate the role of copper acquisition through Ctr1 in normal growth and development. Three distinct Drosophila Ctr1 genes (Ctr1A, Ctr1B, and Ctr1C) have been identified, which have unique expression patterns over the course of development. Interestingly, Ctr1B, which is expressed exclusively during the late embryonic and larval stages of development, is transcriptionally activated in response to nutritionally induced copper deprivation and down-regulated in response to copper adequacy. The generation of Ctr1B mutant flies results in decreased larval copper accumulation, marked body pigmentation defects that parallel defects in tyrosinase activity, and specific developmental arrest under conditions of both nutritional copper limitation and excess. These studies establish that copper acquisition through the Drosophila Ctr1B transporter is crucial for normal growth and in early and specific stages of metazoan development.

Reciprocal functions of Cryptococcus neoformans copper homeostasis machinery during pulmonary infection and meningoencephalitis

“…Ctr1 and Ctr4 are independent and functionally redundant Cu þ importers whose expression is regulated by Cu 12,32 . The recently published nutrient-dependent phenotype of the C. neoformans ctr4D mutant is of great interest but unexpected 18 , and this phenotype has never been observed in other organisms, including Saccharomyces cerevisiae, Candida albicans, Schizosaccharomyces pombe, Aspergillus fumigatus, Drosophila and mice 8,[33][34][35][36][37] . Interestingly, the nutrient phenotype of CTR4 in C. neoformans has not been reported in other studies.…”

Drosophila Ctr1A Functions as a Copper Transporter Essential for Development

“…Drosophila Ctr1A, Ctr1B, and Ctr1C each possess the following three structural features characteristic of all known Ctr family members: three transmembrane domains, a methionine residue preceding the first transmembrane domain, and an MXXXM motif within the second transmembrane domain. Additionally, expression of each Drosophila Ctr1 protein can rescue a yeast strain deficient in high affinity copper uptake, and expression of Ctr1A and Ctr1B stimulates copper uptake in S2 cells (29).…”

Eukaryotic CTR Copper Uptake Transporters Require Two Faces of the Third Transmembrane Domain for Helix Packing, Oligomerization, and Function

“…Initial copper uptake into cells occurs through the CTR 1 family of integral membrane proteins, which function in copper uptake in organisms as diverse as yeast, plants, and metazoans including mice and humans (9 -12). A large subset of the CTRs representing a wide range of evolutionary origin including Candida albicans CTR1, Arabidopsis thaliana COPT1, Schizosaccharomyces pombe CTR4/5, fly CTR1, lizard CTR1, mouse CTR1, and human CTR1 complement a respiratory defect in Saccharomyces cerevisiae that lack high affinity copper uptake systems (11)(12)(13)(14)(15)(16)(17). This ability of numerous CTR proteins to functionally replace endogenous S. cerevisiae Ctr1p and Ctr3p has led to a model in which CTRs themselves act as transporters for copper ions across the plasma membrane.…”