Metallochaperone

Figure 7.29 Wavefunction, Inc. Spartan 02 for Windows representation of the Hahl metallochaperone from reference 118. X-ray data deposited as PDB code 1FEE. See text for visualization details. Printed with permission of Wavefunction, Inc., Irvine, CA. (See color plate.)...

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... 

Figure 3.9 Proposed mechanism of copper insertion into SOD1 by its metallochaperone CCS. (From Culotta et al., 2006. Copyright 2006, with permission from Elsevier.)...

As we will discuss later, in Chapter 8, free copper levels are extremely low within cells because the copper is bound to a family of metallochaperones, which are subsequently involved in the incorporation of copper into copper-containing proteins. The mechanism proposed for copper insertion into the Cu/Zn superoxide dismutase, SOD1, is presented in Figure 3.9. The copper chaperone, CCS, acquires copper as Cu+ from a copper transporter and then docks with the reduced dithiol form of SOD1 (Steps I and II) to give a docked... 

AP has a very effective binding domain for copper in its N-terminal domain and can bind copper in nanomolar amounts (Figure 18.15). It is unclear whether APP or AP when associated with copper, are in fact neuronal metallochaperones. Knock out and knock in mice for APP show that in the former, cerebral cortex copper levels are increased, whereas in the latter reduced copper levels were found. Copper was also influential in APP processing in the cell copper will reduce levels of Ap and cause an increase in the secretion of the APP ectodomain. 

Colpas GJ, Brayman TG, Ming L-J, Hausinger RP. 1999. Identification of metalbinding residues in the Klebsiella aerogenes urease nickel metallochaperone, UreE. Biochemistry 38 4078-88. 

Intracellular distribution of essential transition metals is mediated by specific metallochaperones and transporters localized in endomembranes. In other words, the major processes involved in hyperaccumulation of trace metals from the contaminated medium to the shoots by hyperaccumulators as proposed by Yang et al. (2005) include bioactivation of metals in the rhizosphere through root-microbial interaction enhanced uptake by metal transporters in the plasma membranes detoxification of metals by distributing metals to the apoplasts such as binding to cell walls and chelation of metals in the cytoplasm with various ligands (such as PCs, metallothioneins, metal-binding proteins) and sequestration of metals into the vacuole by tonoplast-located transporters. 

Fig. 1. Comparison of structures of the apo-CopZ and Hg-Atxl metallochaperones irom. Enterococcus hirae and Saccharoniyces cerevisiae, respectively (Rosenzweigeta/., 1999 Wimmer et al., 1999). In the HgAtxl structure the Hg(ll) atom (shown as a dark ball) is ligated by two cysteines (the sulfurs in the side chains are shown as smaller balls). The coordination of the Hg(II) is linear a similar coordination geometry is expected for Cu(I). In the CopZ structure the two corresponding cysteinyl residues shown by arrows are not in the proper orientation to ligate Cu(I). A limited structural rearrangement is expected in the loop to permit linear coordination as seen in Hg-Atxl.

The En. hirae CopY is a transcriptional repressor that limits expression of the CopA and CopB P-type ATPases in cells cultured in medium containing minimal Cu(II) levels (Odermatt and Solioz, 1995). An increase in medium Cu(II) levels results in Cu ion uptake, routing of the Cu(I) ions to CopY by the CopZ metallochaperone, and the subsequent dissociation of CuCopY from the copA and copB genes (Strausak and Solioz, 1997). 

Since both Acel and Mad reside within the nucleus, Cu(I) translocation to the nucleus must occur for metalloregulation to proceed. Yeast cells contain metallochaperones that shuttle Cu(I) ions to distinct destinations, so it is predicted that a shuttle mechanism exists for Cu(I) ion delivery to the nucleus. However, no candidate nuclear copper metallochaperones have been identified. 

Fig. 4. (A) Schematic representation of the occurrence of CxxC motifs in various proteins. The polypeptide chains are drawn to scale as boxes. Transmembrane helices are indicated by empty rectangles and CxxC motifs by filled rectangles. (B) Ribbon model of the structure of CopZ. The position of the copper ion is inferred. Other metallochaperones and the CopZ-like building blocks shown in (A) probably all have a very similar structure.

---