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J. Biol. Chem., Vol. 280, Issue 35, 30956-30962, September 2, 2005

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Two Different Zinc Transport Complexes of Cation Diffusion Facilitator Proteins Localized in the Secretory Pathway Operate to Activate Alkaline Phosphatases in Vertebrate Cells^*

Tomoyuki Suzuki, Kaori Ishihara, Hitoshi Migaki, Kengo Ishihara¶, Masaya Nagao, Yuko Yamaguchi-Iwai, and Taiho Kambe||

From the Division of Life Science, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan and the ^¶Department of Food and Nutrition, School of Life Studies, Sugiyama Jogakuen University, Nagoya 464-8662, Japan

Zinc is an essential component for the 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 showed recently (Suzuki, T., Ishihara, K., Migaki, H., Matsuura, W., Kohda, A., Okumura, K., Nagao, M., Yamaguchi-Iwai, Y., and Kambe, T. (2005) J. Biol. Chem. 280, 637-643) that zinc transporters, ZnT5 and ZnT7, are required for the activation of zinc-requiring enzymes, alkaline phosphatases (ALPs), by transporting zinc into the lumens of the Golgi apparatus and the vesicular compartments where ALPs locate and converting apoALPs to holoALPs. 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 ALP 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 alone. Furthermore, co-immunoprecipitation studies revealed that ZnT5 and ZnT6 formed hetero-oligomers, whereas 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 ALPs.

Received for publication, June 24, 2005 , and in revised form, June 29, 2005.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY986776.

^* This work was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to Y. Y.-I. and T. K.) and by the Sasakawa Scientific Research Grant from The Japan Science Society (to T. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data in the form of a figure presenting experimental strategy and targeting constructs.

Supported by a grant from the 21st Century Center of Excellence Program of the Ministry of Education, Culture, Sports, Science and Technology of Japan to the Graduate School of Biostudies and Institute for Virus Research, Kyoto University.

^|| To whom correspondence should be addressed. Tel.: 81-75-753-6273; Fax: 81-75-753-6274; E-mail: kambe1{at}kais.kyoto-u.ac.jp.

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