A model for the incorporation of metal from the copper chaperone CCS into Cu,Zn superoxide dismutase.
BACKGROUND
Recent studies have identified the human copper chaperone CCS as the presumed factor responsible for copper incorporation into superoxide dismutase (SOD). A lack of knowledge of the chaperone's three-dimensional structure has prevented understanding of how the copper might be transferred.


RESULTS
The three-dimensional structure of CCS was homology modelled using the periplasmic protein from the bacterial mercury-detoxification system and the structure of one subunit of the human SOD dimeric enzyme as templates. On the basis of the three-dimensional model, a mechanism for the transfer of copper from CCS to SOD is proposed that accounts for electrostatic acceptor recognition, copper storage and copper-transfer properties.


CONCLUSIONS
The proposed model identifies a path for copper transfer based on the presence of different metal sites characterized by sulphur ligands. Such a model permits the development of strategies able to interfere with copper incorporation in SOD, providing a possible way to prevent or arrest degeneration in the fatal motor neuron disorder amyotrophic lateral sclerosis.
Falconi
M
M
Instituto Nazionale di Fisica della Materia, e Dipartimento di Biologia, Universita' di Roma Tor Vergata, Rome, Italy.
Iovino
M
M
Desideri
A
A
D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry; D002352:Carrier Proteins / Q000737:chemistry; D003300:Copper / Q000737:chemistry*; D006801:Humans; D008956:Models, Chemical; D018832:Molecular Chaperones / Q000737:chemistry*; D008969:Molecular Sequence Data; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011506:Proteins; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D013482:Superoxide Dismutase / Q000737:chemistry*
D001426:Bacterial Proteins; C114678:CCS protein, human; D002352:Carrier Proteins; C086060:MerP protein, Bacteria; D018832:Molecular Chaperones; D011506:Proteins; D003300:Copper; D013482:Superoxide Dismutase