ArticleThe Biochemical journal2016
The PP-motif in luminal loop 2 of ZnT transporters plays a pivotal role in TNAP activation.
Article in The Biochemical journal, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 24 citations in OpenAlex.
- Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface.Nature communications · 2023Article
- Zinc and Zinc Transporters in Dermatology.International journal of molecular sciences · 2022Review
- 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
- Why and how to investigate the role of protein phosphorylation in ZIP and ZnT zinc transporter activity and regulation.Cellular and molecular life sciences : CMLS · 2020Review
- Detailed analyses of the crucial functions of Zn transporter proteins in alkaline phosphatase activation.The Journal of biological chemistry · 2020Article
- Zinc homeostasis in the secretory pathway in yeast.Current opinion in chemical biology · 2020Review
- 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
- 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 transporters belonging to the Cation Diffusion Facilitator (CDF) family have complementary roles in transporting zinc out of the cytosol.PLoS genetics · 2018Article
- Understanding the Contribution of Zinc Transporters in the Function of the Early Secretory Pathway.International journal of molecular sciences · 2017Review
- Physiological roles of zinc transporters: molecular and genetic importance in zinc homeostasis.The journal of physiological sciences : JPS · 2017Review
- Dissecting the Process of Activation of Cancer-promoting Zinc-requiring Ectoenzymes by Zinc Metalation Mediated by ZNT Transporters.The Journal of biological chemistry · 2017Article
- Zinc transporters and their functional integration in mammalian cells.The Journal of biological chemistryReview
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Authors and funding
15 authors at 3 institutions in 2 countries.
Funding
Abstract
Secretory and membrane-bound zinc-requiring enzymes are thought to be activated by binding zinc in the early secretory pathway. One such enzyme, tissue-non-specific alkaline phosphatase (TNAP), is activated through a two-step mechanism, via protein stabilization and subsequent enzyme activation through metalation, by ZnT5-ZnT6 heterodimers or ZnT7 homodimers. However, little is known about the molecular basis underlying the activation process. In the present study, we found that the di-proline motif (PP-motif) in luminal loop 2 of ZnT5 and ZnT7 is important for TNAP activation. TNAP activity was significantly reduced in cells lacking ZnT5-ZnT6 heterodimers and ZnT7 homodimers [triple knockout (TKO) cells]. The decreased TNAP activity was restored by expressing hZnT5 with hZnT6 or hZnT7, but significantly less so (almost 90% less) by expressing mutants thereof in which the PP-motif was mutated to alanine (PP-AA). In TKO cells, overexpressed hTNAP was not completely activated, and it was converted less efficiently into the holo form by expressing a PP-AA mutant of hZnT5 with hZnT6, whose defects were not restored by zinc supplementation. The zinc transport activity of hZnT7 was not significantly impaired by the PP-AA mutation, indicating that the PP-motif is involved in the TNAP maturation process, although it does not control zinc transport activity. The PP-motif is highly conserved in ZnT5 and ZnT7 orthologues, and its importance for TNAP activation is conserved in the Caenorhabditis elegans hZnT5 orthologue CDF5. These results provide novel molecular insights into the TNAP activation process in the early secretory pathway.
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