ArticleThe Journal of biological chemistry2011
Tissue nonspecific alkaline phosphatase is activated via a two-step mechanism by zinc transport complexes in the early secretory pathway.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40 citing papers in PubMed, 70 citations in OpenAlex.
- Functional characterization of a novel ZIP8 variant causing impaired manganese homeostasis and congenital disorders of glycosylation.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2026Article
- Zinc-redox crosstalk regulates proteostasis in the endoplasmic reticulum.Nature communications · 2026Article
- Modulation of ZnT-1 by Let7a unveils a therapeutic potential in amyotrophic lateral sclerosis.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Article
- SLC30 (ZnT) and SLC39 (ZIP) zinc transporter families: from gatekeepers of zinc homeostasis to promoters of tumorigenesis and targets for clinical therapy.Frontiers in immunology · 2025Review
- Metalation and activation of ZnBiophysics reviews · 2023Review
- Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface.Nature communications · 2023Article
- Pigmentation and TYRP1 expression are mediated by zinc through the early secretory pathway-resident ZNT proteins.Communications biology · 2023Article
- Zinc transport via ZNT5-6 and ZNT7 is critical for cell surface glycosylphosphatidylinositol-anchored protein expression.The Journal of biological chemistry · 2022Article
- Regulation of zinc-dependent enzymes by metal carrier proteins.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2022Review
- Zinc Signaling in the Mammary Gland: For Better and for Worse.Biomedicines · 2021Review
- Detailed analyses of the crucial functions of Zn transporter proteins in alkaline phosphatase activation.The Journal of biological chemistry · 2020Article
- Transcription factors and transporters in zinc homeostasis: lessons learned from fungi.Critical reviews in biochemistry and molecular biology · 2020Review
- Zinc transporter 1 (ZNT1) expression on the cell surface is elaborately controlled by cellular zinc levels.The Journal of biological chemistry · 2019Article
- Zinc-dependent activation of the Pho8 alkaline phosphatase inThe Journal of biological chemistry · 2019Article
- An extracellular histidine-containing motif in the zinc transporter ZIP4 plays a role in zinc sensing and zinc-induced endocytosis in mammalian cells.The Journal of biological chemistry · 2019Article
- Zinc regulates ERp44-dependent protein quality control in the early secretory pathway.Nature communications · 2019Article
- Evaluation of the roles of the cytosolic N-terminus and His-rich loop of ZNT proteins using ZNT2 and ZNT3 chimeric mutants.Scientific reports · 2018Article
- Zinc Transporter Proteins.Neurochemical research · 2018Review
- Zinc deficiency causes delayed ATP clearance and adenosine generation in rats and cell culture models.Communications biology · 2018Article
- Understanding the Contribution of Zinc Transporters in the Function of the Early Secretory Pathway.International journal of molecular sciences · 2017Review
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Authors and funding
12 authors at 6 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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