Tissue Nonspecific Alkaline Phosphatase is Activated Via a Two-step Mechanism by Zinc Transport Complexes in the Early Secretory Pathway

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2011 Mar 16

PMID 21402707

Citations 36

Authors

Ayako Fukunaka

Yayoi Kurokawa

Fumie Teranishi

Israel Sekler

Kimimitsu Oda

M Leigh Ackland

Victor Faundez

Makoto Hiromura

Seiji Masuda

Masaya Nagao

Shuichi Enomoto

Taiho Kambe

Affiliations

Soon will be listed here.

Abstract

A number of enzymes become functional by binding to zinc during their journey through the early secretory pathway. The zinc transporters (ZnTs) located there play important roles in this step. We have previously shown that two zinc transport complexes, ZnT5/ZnT6 heterodimers and ZnT7 homo-oligomers, are required for the activation of alkaline phosphatases, by converting them from the apo- to the holo-form. Here, we investigated the molecular mechanisms of this activation. ZnT1 and ZnT4 expressed in chicken DT40 cells did not contribute to the activation of tissue nonspecific alkaline phosphatase (TNAP). The reduced activity of TNAP in DT40 cells deficient in both ZnT complexes was not restored by zinc supplementation nor by exogenous expression of other ZnTs that increase the zinc content in the secretory pathway. Moreover, we showed that expression of ZnT5/ZnT6 heterodimers reconstituted with zinc transport-incompetent ZnT5 mutant failed to restore TNAP activity but could stabilize the TNAP protein as the apo-form, regardless of zinc status. These findings demonstrate that TNAP is activated not simply by passive zinc binding but by an elaborate two-step mechanism via protein stabilization followed by enzyme conversion from the apo- to the holo-form with zinc loaded by ZnT complexes in the early secretory pathway.

Citing Articles

Metalation and activation of Zn enzymes via early secretory pathway-resident ZNT proteins.

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References

Fang Y, Sugiura R, Ma Y, Yada-Matsushima T, Umeno H, Kuno T . Cation diffusion facilitator Cis4 is implicated in Golgi membrane trafficking via regulating zinc homeostasis in fission yeast. Mol Biol Cell. 2008; 19(4):1295-303. PMC: 2291430. DOI: 10.1091/mbc.e07-08-0805. View

Kambe T, Yamaguchi-Iwai Y, Sasaki R, Nagao M . Overview of mammalian zinc transporters. Cell Mol Life Sci. 2004; 61(1):49-68. PMC: 11138893. DOI: 10.1007/s00018-003-3148-y. View

Michalczyk A, Allen J, Blomeley R, Ackland M . Constitutive expression of hZnT4 zinc transporter in human breast epithelial cells. Biochem J. 2002; 364(Pt 1):105-13. PMC: 1222551. DOI: 10.1042/bj3640105. View

Seals D, Courtneidge S . The ADAMs family of metalloproteases: multidomain proteins with multiple functions. Genes Dev. 2003; 17(1):7-30. DOI: 10.1101/gad.1039703. View

Fujimori A, Tachiiri S, Sonoda E, Thompson L, DHAR P, Hiraoka M . Rad52 partially substitutes for the Rad51 paralog XRCC3 in maintaining chromosomal integrity in vertebrate cells. EMBO J. 2001; 20(19):5513-20. PMC: 125654. DOI: 10.1093/emboj/20.19.5513. View

Vembar S, Brodsky J . One step at a time: endoplasmic reticulum-associated degradation. Nat Rev Mol Cell Biol. 2008; 9(12):944-57. PMC: 2654601. DOI: 10.1038/nrm2546. View

Ellis C, Wang F, MacDiarmid C, Clark S, Lyons T, Eide D . Zinc and the Msc2 zinc transporter protein are required for endoplasmic reticulum function. J Cell Biol. 2004; 166(3):325-35. PMC: 2172251. DOI: 10.1083/jcb.200401157. View

Purkerson J, Schwartz G . The role of carbonic anhydrases in renal physiology. Kidney Int. 2006; 71(2):103-15. DOI: 10.1038/sj.ki.5002020. View

Ranaldi G, Perozzi G, Truong-Tran A, Zalewski P, Murgia C . Intracellular distribution of labile Zn(II) and zinc transporter expression in kidney and MDCK cells. Am J Physiol Renal Physiol. 2002; 283(6):F1365-75. DOI: 10.1152/ajprenal.00094.2002. View

10.

Haremaki T, Fraser S, Kuo Y, Baron M, Weinstein D . Vertebrate Ctr1 coordinates morphogenesis and progenitor cell fate and regulates embryonic stem cell differentiation. Proc Natl Acad Sci U S A. 2007; 104(29):12029-34. PMC: 1924542. DOI: 10.1073/pnas.0701413104. View

11.

Fukada T, Civic N, Furuichi T, Shimoda S, Mishima K, Higashiyama H . The zinc transporter SLC39A13/ZIP13 is required for connective tissue development; its involvement in BMP/TGF-beta signaling pathways. PLoS One. 2008; 3(11):e3642. PMC: 2575416. DOI: 10.1371/journal.pone.0003642. View

12.

Suzuki T, Ishihara K, Migaki H, Ishihara K, Nagao M, Yamaguchi-Iwai Y . Two different zinc transport complexes of cation diffusion facilitator proteins localized in the secretory pathway operate to activate alkaline phosphatases in vertebrate cells. J Biol Chem. 2005; 280(35):30956-62. DOI: 10.1074/jbc.M506902200. View

13.

Chimienti F, Devergnas S, Pattou F, Schuit F, Garcia-Cuenca R, Vandewalle B . In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion. J Cell Sci. 2006; 119(Pt 20):4199-206. DOI: 10.1242/jcs.03164. View

14.

Natesh R, Schwager S, Sturrock E, Acharya K . Crystal structure of the human angiotensin-converting enzyme-lisinopril complex. Nature. 2003; 421(6922):551-4. DOI: 10.1038/nature01370. View

15.

Lazarczyk M, Pons C, Mendoza J, Cassonnet P, Jacob Y, Favre M . Regulation of cellular zinc balance as a potential mechanism of EVER-mediated protection against pathogenesis by cutaneous oncogenic human papillomaviruses. J Exp Med. 2007; 205(1):35-42. PMC: 2234378. DOI: 10.1084/jem.20071311. View

16.

Ellgaard L, Helenius A . Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Biol. 2003; 4(3):181-91. DOI: 10.1038/nrm1052. View

17.

Ito M, Amaya Y, Amizuka N, Ozawa H, Omura S, Ikehara Y . Possible interference between tissue-non-specific alkaline phosphatase with an Arg54-->Cys substitution and acounterpart with an Asp277-->Ala substitution found in a compound heterozygote associated with severe hypophosphatasia. Biochem J. 2000; 348 Pt 3:633-42. PMC: 1221107. View

18.

Inoue K, Matsuda K, Itoh M, Kawaguchi H, Tomoike H, Aoyagi T . Osteopenia and male-specific sudden cardiac death in mice lacking a zinc transporter gene, Znt5. Hum Mol Genet. 2002; 11(15):1775-84. DOI: 10.1093/hmg/11.15.1775. View

19.

Ishida Y, Komaru K, Ito M, Amaya Y, Kohno S, Oda K . Tissue-nonspecific alkaline phosphatase with an Asp(289)-->Val mutation fails to reach the cell surface and undergoes proteasome-mediated degradation. J Biochem. 2003; 134(1):63-70. DOI: 10.1093/jb/mvg114. View

20.

Jirakulaporn T, Muslin A . Cation diffusion facilitator proteins modulate Raf-1 activity. J Biol Chem. 2004; 279(26):27807-15. DOI: 10.1074/jbc.M401210200. View