| Abstract
| - The human copper chaperone for superoxide dismutase (hCCS) delivers the essential copperion cofactor to copper,zinc superoxide dismutase (SOD1), a key enzyme in antioxidant defense. Mutationsin SOD1 are linked to familial amyotrophic lateral sclerosis (FALS), a fatal neurodegenerative disorder.The molecular mechanisms by which SOD1 is recognized and activated by hCCS are not understood. Tobetter understand this biochemical pathway, we have determined the X-ray structure of the largest domainof hCCS (hCCS Domain II) to 2.75 Å resolution. The overall structure is closely related to that of itstarget enzyme SOD1, consisting of an eight-stranded β-barrel and a zinc-binding site formed by twoextended loops. The first of these loops provides the ligands to a bound zinc ion, and is analogous to thezinc subloop in SOD1. The second structurally resembles the SOD1 electrostatic channel loop, but lacksmany of the residues important for catalysis. Like SOD1 and yCCS, hCCS forms a dimer using a highlyconserved interface. In contrast to SOD1, however, the hCCS structure does not contain a copper ionbound in the catalytic site. Notably, the structure reveals a single loop proximal to the dimer interfacewhich is unique to the CCS chaperones.
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