Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development

Abstract

The trace metal copper (Cu) plays an essential role in biology as a cofactor for many enzymes that include Cu, Zn superoxide dismutase, cytochrome oxidase, ceruloplasmin, lysyl oxidase, and dopamine ␤-hydroxylase. Consequently, Cu transport at the cell surface and the delivery of Cu to intracellular compartments are critical events for a wide variety of biological processes. The components that orchestrate intracellular Cu trafficking and their roles in Cu homeostasis have been elucidated by the studies of model microorganisms and by the characterizations of molecular basis of Cu-related genetic diseases, including Menkes disease and Wilson disease. However, little is known about the mechanisms for Cu uptake at the plasma membrane and the consequences of defects in this process in mammals. Here, we show that the mouse Ctr1 gene encodes a component of the Cu transport machinery and that mice heterozygous for Ctr1 exhibit tissue-specific defects in copper accumulation and in the activities of copper-dependent enzymes. Mice completely deficient for Ctr1 exhibit profound growth and developmental defects and die in utero in mid-gestation. These results demonstrate a crucial role for Cu acquisition through the Ctr1 transporter for mammalian Cu homeostasis and embryonic development.

XIAP: Cell death regulation meets copper homeostasis

“…Copper is transported into the cell via the high affinity Copper transporter (Ctr) proteins, which are highly conserved from yeast to humans [37,38] (Figure 3). All Ctr proteins contain three transmembrane domains, and most possess extracellular, methionine rich motifs (MxxM, MxM) at the amino terminal and an additional MxxxM motif in the second transmembrane domain [39].…”

“…Two Ctr homologs, Ctr1 and Ctr2, have also been identified in vertebrates, and of these, Ctr1 is the main protein responsible for intracellular copper transport. It is ubiquitously expressed and is absolutely required for embryonic development, as Ctr1-deficient mice die halfway through gestation due to growth retardation and impaired development of the neuroectoderm and mesoderm [37]. The exact function of Ctr2 in vertebrates remains unclear although the same protein in yeast has been shown to play an important role in mobilizing vacuolar copper stores [40].…”

Les bases moléculaires de l’approvisionnement en cuivre

“…Les études chez la souris prouvent à quel point l'incorporation du cuivre est capitale pour le développement de l'organisme. Les souris qui ont subi l'inactivation des deux allèles CTR1 codant pour le transporteur responsable de l'assimilation du cuivre meurent avant d'atteindre le milieu de la phase embryonnaire [9]. Comme pour le transporteur humain, le Ctr1 murin a tout d'abord été caractérisé à la suite de son expression chez la levure.…”

Posttranslational regulation of copper transporters

“…Copper import in mammals is primarily mediated by the copper transporter (CTR) family of proteins that comprises the homologous CTR1 and CTR2. CTR1 is absolutely required for dietary copper absorption and is essential for cellular copper uptake [1][2][3][4][5][6][7]. Cellular copper export is equally important and is dependent on ATP7A and ATP7B [8][9][10][11][12].…”

“…Overexpression of hCTR1 in several cell lines results in a substantial, specific, and saturable induction of cellular copper import with a K m of approximately 1-5 lM [7,35,39]. Ctr1 knockout mice died during midgestation, indicating an essential role for Ctr1 in embryonic development [2,4]. Interestingly, Ctr1 ?/-mice that survived the embryonic stages displayed copper deficiencies in brain tissue, indicating that Ctr1 is indispensable for copper transport in mammals [2].…”