Function, structure, and mechanism of intracellular copper trafficking proteins.
Genetic, biochemical, and spectroscopic studies have established a new function for an intracellular protein, i.e., guiding and inserting a copper cofactor into the active site of a target enzyme. Studies of these new proteins have revealed a fundamental aspect of copper physiology, namely the vast overcapacity of the cytoplasm for copper sequestration. This finding framed the mechanistic, energetic, and structural aspects of intracellular copper trafficking proteins. One hallmark of the copper chaperones is the similarity of the protein fold between the chaperone and its target enzyme. The surface residues presented by each partner, however, are quite different, and some initial findings concerning the complementarity of these interfaces have led to mechanistic insights. The copper chaperones appear to lower the activation barrier for metal transfer into specific protein-binding sites. The manner in which they facilitate metal insertion appears to involve a docking of the metal donor and acceptor sites in close proximity to one another. Although the intimate mechanism is still open, it appears that a low activation barrier for metal transfer is achieved by a network of coordinate-covalent, electrostatic, and hydrogen bonding interactions in the vicinity of the metal-binding site itself.
Huffman
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Department of Chemistry, Northwestern University, Evanston, Illinois 60208-3113, USA. d-huffman@northwestern.edu
O'Halloran
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D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001692:Biological Transport; D002352:Carrier Proteins; D027682:Cation Transport Proteins / Q000737:chemistry / Q000378:metabolism; D017124:Conserved Sequence; D003300:Copper / Q000378:metabolism*; D000079922:Copper Transport Proteins; D003576:Electron Transport Complex IV / Q000378:metabolism; D005656:Fungal Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D056511:Metallochaperones; D008667:Metalloproteins / Q000737:chemistry / Q000378:metabolism; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D029701:Saccharomyces cerevisiae Proteins; D013482:Superoxide Dismutase / Q000378:metabolism
C474500:ATOX1 protein, human; C093341:ATX1 protein, S cerevisiae; C092974:CCC2 protein, S cerevisiae; C491006:COX17 protein, human; D002352:Carrier Proteins; D027682:Cation Transport Proteins; D000079922:Copper Transport Proteins; D005656:Fungal Proteins; D056511:Metallochaperones; D008667:Metalloproteins; D018832:Molecular Chaperones; D029701:Saccharomyces cerevisiae Proteins; D003300:Copper; D013482:Superoxide Dismutase; D003576:Electron Transport Complex IV; D000251:Adenosine Triphosphatases