Superoxide dismutase metallochaperones

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... 

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... 

Intracellular transport of metal ions has been a very well studied research area in the last few years. The most often-cited case of this transport involves copper transport in yeast by the copper metallochaperones 24, 25). Cu(I) enters the cytoplasm of yeast via copper transport receptors, and Cu(I) is bound by one of three transport proteins Lys7, Atxl, or Cox 17. Lys7 delivers copper to CuZn superoxide dismutase, Atxl delivers copper to ccc2 that activates an Fe(II) uptake system, and Cox 17 delivers copper to the mitochondria for the ultimate uptake into cytochrome c oxidase. A similar copper transport system has been reported in humans (26), and there may be a system in bacteria as well (27). Metal ion transport systems are known for iron, nickel, and manganese 24, 25, 28). However, no cytoplasmic Zn(II) transporters have been identified in... 

We believe that using the genetic approaches that were used to identify other metallochaperones to discover any Zn(II) metallochaperones in E. coli will not be successful. In yeast/ . coli there are less than ten copper-containing proteins 47), and most of these proteins are involved with oxygen/reactive oxygen species chemistry. In constrast, there could be almost 200 Zn(II)-metalloproteins that have numerous catalytic and structural roles 48). The choice of a deficient phenotype that could be linked directly to Zn(II) would be very challenging. The choice of superoxide dismutase deficiency (CuZn enzyme) would probably not be successful in E. coli since there are two other... 

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