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Papers In Press, published online ahead of print July 1, 2005
Department of Applied Molecular Biology, Kyoto University, Kyoto, Kyoto 606-8502
Corresponding Author: kambe1{at}kais.kyoto-u.ac.jp
Zinc is an essential component for catalytic activity of numerous zinc-requiring enzymes. However, until recently little has been known about the molecules involved in the pathways required for supplying zinc to these enzymes. We recently showed that two zinc transporters, ZnT5 and ZnT7, are required for the activation of zinc-requiring enzymes, alkaline phosphatases (ALPs), by transporting zinc into the lumens of Golgi apparatus and the vesicular compartments where they locate and converting apo- to holo-form of enzymes inside of these subcellular compartments. ZnT6 is also located in the vesicular compartments like ZnT5 and ZnT7. However, the functions of ZnT6 and relationships among these three transporters have not been characterized yet. Here, we characterized the cellular function of ZnT6 together with ZnT5 and ZnT7 by gene-targeting studies using DT40 cells. ZnT6-deficient DT40 cells showed low tissue-nonspecific ALP (TNAP) activity, suggesting that ZnT6 is required for the activation of zinc-requiring enzymes like ZnT5 and ZnT7. Combined disruptions of three transporter genes and re-expressions of transgenes revealed that ZnT5 and ZnT6 work in the same pathway whereas ZnT7 acts solely. Furthermore, co-immunopreciptation studies revealed that ZnT5 and ZnT6 formed hetero-oligomers while ZnT7 formed homo-oligomers. Interestingly, the Ser-rich loop in ZnT6, a potential zinc-binding site, was dispensable for the zinc-supplying function of ZnT5/ZnT6 hetero-oligomers, suggesting that the His-rich loop in ZnT5 may be important for zinc-binding and that the loop in ZnT6 may acquire another function in the hetero-oligomer formation. These results suggest that two different zinc transport complexes operate to activate TNAP.
J. Biol. Chem, 10.1074/jbc.M506902200
Submitted on June 24, 2005
Revised on June 29, 2005
Accepted on July 1, 2005
Two different zinc transport complexes of cation diffusion facilitator proteins localized in the secretory pathway operate to activate alkaline phosphatase in vertebrate cells
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