Cytoplasmic copper chaperone

Metallochaperones (like ATOX 1) transfer copper to the site of synthesis of copper containing proteins (Rae et al., 1999 Huffman and O Halloran, 2002). The cytoplasmic copper chaperone ATOXl is required for copper delivery to ATP7B by direct protein-protein interaction (Hamza et al., 1999 Walker et al., 2002). ATP7B is abundantly expressed in hepatocytes and is localized in these cells to the late secretory pathway, predominantly the tran -Golgi network. With increasing intracellular copper concentrations, this ATPase traffics to a cytoplasmic vesicular compartment that distributes near the canaUcular membrane in polarized hepatocytes and... 

Figure 12.2 Copper chaperone function, (a) Copper homeostasis in Enterococcus hirae is affected by the proteins encoded by the cop operon. CopA, Cu1+-import ATPase CopB, Cu1+-export ATPase CopY, Cu1+-responsive repressor copZ, chaperone for Cu1+ delivery to CopY. (b) The CTR family of proteins transports copper into yeast cells. Atxlp delivers copper to the CPx-type ATPases located in the post Golgi apparatus for the maturation of Fet3p. (c) Coxl7p delivers copper to the mitochondrial intermembrane space for incorporation into cytochrome c oxidase (CCO). (d) hCTR, a human homologue of CTR, mediates copper-ion uptake into human cells. CCS delivers copper to cytoplasmic Cu/Zn superoxide dismutase (SOD1). Abbreviations IMM, inner mitochondrial membrane OMM, outer mitochondrial membrane PM, plasma membrane PGV, post Golgi vessel. Reprinted from Harrison et al., 2000. Copyright (2000), with permission from Elsevier Science.

As stated previously, the total normal cytoplasmic free copper concentration is less than 10 18 M or less than one copper ion per cell. In thermodynamic terms, almost all hydrated copper ions are immediately and tightly coordinated by amino acids or biopolymers—peptides, proteins, and other species with free sulfur ligands. An excess of copper ions activates metallothionein synthesis for storage or removal of the excess. Copper chaperones mediate transfer of copper ions from extracellular or storage locations to their target proteins. Instability of copper ion concentrations in vivo results in various disease states. Three of these—FALS, Menkes, and Wilson s diseases—are described below. 

We will discuss in more detail in Chapter 8 how intracellular copper levels are maintained at extremely low levels by a series of copper chaperone proteins, which sequester newly assimilated copper within the cytoplasm of cells and deliver it in a targeted manner to be incorporated into specific copper-containing proteins. While copper uptake across the gastrointestinal tract is poorly understood—most probably utilising the divalent cation transporter... 

Bacterial copper proteins are found only in the plasma membrane (Gram-positive bacteria) or in the plasma membrane and the periplasm (Gram-negative bacteria), not in the bacterial cytoplasm. However, cyanobacteria do have copper proteins in their cytoplasm. These important photosynthetic bacteria require copper for plastocyanin, which plays a critical role in the photosynthetic electron transport chain. Both plastocyanin and cytochrome c oxidase are found in the thylakoid compartments within the cytoplasm. In Synechocystis, the Cu(I) Pie-ATPase CtaA imports Cu(I). A second ATPase, PacS, imports Cu(I) into the thylakoid, and the Atxl-like copper chaperone ScAtxl is believed to deliver Cu(I) from CtaA to PacS (Fig. 8.6). 

Fig. 1. Schematic overview of copper trafficking and homeostasis inside the yeast cell. The actions of Mad and Ace 1, copper-dependent metalloregulatory transcription factors, control the production of copper import [copper transporter (Ctr) and reductase (Fre)] and detoxification/sequestration [metallothionein (MT)] machineries, respectively. Three chaperone-mediated delivery pathways are shown. Atxl shuttles Cu(I) to the secretory pathway P-type ATPase Ccc2 (right). CCS delivers Cu(I) to the cytoplasmic enzyme copper-zinc superoxide dismutase (SOD) (left). Coxl7 shuttles Cu(I) to cytochrome c oxidase (CCO) in the mitochondria (bottom). Mitochondrial proteins Scol and Sco2 may also play a role in copper delivery to the CuA and CuB sites of CCO. Copper metabolism and iron metabolism are linked through the actions of Fet3, a copper-containing ferroxidase required to bring iron into the cell (lower right) (see text).

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