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J. Biol. Chem., Vol. 280, Issue 1, 637-643, January 7, 2005

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Zinc Transporters, ZnT5 and ZnT7, Are Required for the Activation of Alkaline Phosphatases, Zinc-requiring Enzymes That Are Glycosylphosphatidylinositol-anchored to the Cytoplasmic Membrane^*

Tomoyuki Suzuki, Kaori Ishihara, Hitoshi Migaki, Wataru Matsuura, Atsushi Kohda¶, Katsuzumi Okumura¶, Masaya Nagao, Yuko Yamaguchi-Iwai, and Taiho Kambe||

From the Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502 and the ^¶Department of Life Science, Faculty of Bioresources, Mie University, Mie 514-8507, Japan

Numerous proteins are properly folded by binding with zinc during their itinerary in the biosynthetic-secretory pathway. Several transporters have been implicated in the zinc entry into secretory compartments from cytosol, but their precise roles are poorly understood. We report here that two zinc transporters (ZnT5 and ZnT7) localized in the secretory apparatus are responsible for loading zinc to alkaline phosphatases (ALPs) that are glycosylphosphatidylinositol-anchored membrane proteins exposed to the extracellular site. Disruption of the ZnT5 gene in DT40 cells decreased the ALP activity to 45% of that in the wild-type cells. Disruption of the ZnT7 gene lowered the ALP activity only by 20%. Disruption of both genes markedly decreased the ALP activity to <5%. Overexpression of human ZnT5 or ZnT7 in DT40 cells deficient in both ZnT5 and ZnT7 genes recovered the ALP activity to the level comparable to that in the wild-type cells. The inactive ALP protein in DT40 cells deficient in both ZnT5 and ZnT7 genes was transported to cytoplasmic membrane like the active ALP protein in the wild-type cells. Thus both ZnT5 and ZnT7 contribute to the conversion of apo-ALP to holo-ALP.

Received for publication, October 1, 2004 , and in revised form, November 2, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY703476 and AY703477.

^* 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 Novartis Foundation (Japan) for the Promotion of Science (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.

Supported by 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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