Chaperones delivery pathways

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).

The sequence for delivery of copper ions to SOD1 passes from the copper transporter (Ctr) by an unknown pathway to the copper chaperone for SOD1 (CCS) and by a studied pathway from CCS to SOD1. The CCS protein has been studied structurally and found to be similar to other copper chaperones such as those discussed above—Atxl and Atoxl (Hahl). Copper chaperone for superoxide dismutase (CCS) differs from other copper metallochaperones in that it folds into three functionally distinct protein domains with the N-terminal end of domain I... 

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... 

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