How Mammalian Cells Acquire Copper: An Essential but Potentially Toxic Metal

Abstract

Cu is an essential micronutrient, and its role in an array of critical physiological processes is receiving increasing attention. Among these are wound healing, angiogenesis, protection against reactive oxygen species, neurotransmitter synthesis, modulation of normal cell and tumor growth, and many others. Free Cu is absent inside cells, and a network of proteins has evolved to deliver this essential, but potentially toxic, metal ion to its intracellular target sites following uptake. Although the total body content is low (∼100 mg), dysfunction of proteins involved in Cu homeostasis results in several well-characterized human disease states. The initial step in cellular Cu handling is its transport across the plasma membrane, a subject of study for only about the last 25 years. This review focuses on the initial step in Cu homeostasis, the properties of the major protein, hCTR1, that mediates Cu uptake, and the status of our understanding of this highly specialized transport system. Although a high-resolution structure of the protein is still lacking, an array of biochemical and biophysical studies have provided a picture of how hCTR1 mediates Cu(I) transport and how Cu is delivered to the proteins in the intracellular milieu. Recent studies provide evidence that the transporter also plays a key protective role in the regulation of cellular Cu via regulatory endocytosis, lowering its surface expression, in response to elevated Cu loads.

The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis

“…copper chloride in vitro or in the anionic copper complex observed in vivo (5)). Significant precedent exists in the literature for the transport of metal-anion complexes in eukaryotic systems, including transport of copper into a number of epithelial cells via anion transporters (37,38). We previously reported an interaction between the copper chelate found in the mitochondrial matrix and Pic2 from yeast (31), and we observed a similar interaction here with recombinant human SLC25A3-A using fluorescence anisotropy.…”

Copper trafficking to the secretory pathway

“…39). Yet, the mechanism of Cu transport by CTR1, especially Cu release into a cytosol, is far from being fully understood.…”

Dynamic internalization and recycling of a metal ion transporter: Cu homeostasis and CTR1, the human Cu+ uptake system

“…The process could be repeated several times, was seen in a wide range of cells, and was an acute regulatory response to elevated medium Cu (Molloy and Kaplan, 2009). CTR1 is a small protein of 190 amino acid residues with three transmembrane segments, a variable extracellular amino terminus and a highly conserved intracellular carboxyl terminus of about 15 residues (Kaplan and Maryon, 2016). During a recent functional mutational analysis, we observed that mutations in the final three highly conserved residues (His-Cys-His) resulted in high rates of transport and the mutant CTR1 did not undergo regulatory endocytosis in elevated Cu (Maryon et al, 2013a).…”