ArticleThe FEBS journal2018
The C-terminal cytosolic domain of the human zinc transporter ZnT8 and its diabetes risk variant.
Article in The FEBS journal, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 41 citations in OpenAlex.
- Complete loss of SLC30A8 in humans improves glucose metabolism and beta cell function.Diabetologia · 2025Article
- Loss-of-function variant of SLC30A8 rs13266634 (C > T) protects against type 2 diabetes by stabilizing ZnT8: Insights from epidemiological and computational analyses.Journal, genetic engineering & biotechnology · 2025Article
- Energy coupling and stoichiometry of ZneLife · 2023Article
- Antiviral activity of zinc against hepatitis viruses: current status and future prospects.Frontiers in microbiology · 2023Review
- Review
- Zinc binding alters the conformational dynamics and drives the transport cycle of the cation diffusion facilitator YiiP.The Journal of general physiology · 2021Article
- Loss of Znt8 function in diabetes mellitus: risk or benefit?Molecular and cellular biochemistry · 2021Review
- Molecular Insight into the Regulation of Vimentin by Cysteine Modifications and Zinc Binding.Antioxidants (Basel, Switzerland) · 2021Article
- Metal transport mechanism of the cation diffusion facilitator (CDF) protein family - a structural perspective on human CDF (ZnT)-related diseases.RSC chemical biology · 2021Review
- Probing the Structure and Function of the Cytosolic Domain of the Human Zinc Transporter ZnT8 with Nickel(II) Ions.International journal of molecular sciences · 2021Article
- Insights into the Dynamics of the Human Zinc Transporter ZnT8 by MD Simulations.Journal of chemical information and modeling · 2021Article
- The role of labile ZnMolecular and cellular biochemistry · 2021Review
- Heterologous Expression and Biochemical Characterization of the Human Zinc Transporter 1 (ZnT1) and Its Soluble C-Terminal Domain.Frontiers in chemistry · 2021Article
- 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
- Article
- C-Terminal Domain of the Human Zinc Transporter hZnT8 Is Structurally Indistinguishable from Its Disease Risk Variant (R325W).International journal of molecular sciences · 2020Article
- Structure/Function Analysis of human ZnT8 (SLC30A8): A Diabetes Risk Factor and Zinc Transporter.Current research in structural biology · 2020Article
- Down-regulation of the islet-specific zinc transporter-8 (ZnT8) protects human insulinoma cells against inflammatory stress.The Journal of biological chemistry · 2019Article
- ZnT8 Haploinsufficiency Impacts MIN6 Cell Zinc Content and β-Cell Phenotype via ZIP-ZnT8 Coregulation.International journal of molecular sciences · 2019Article
- Loss of ZnT8 function protects against diabetes by enhanced insulin secretion.Nature genetics · 2019Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
A significant aspect of the control of cellular zinc in eukarya is its subcellular re-distribution. One of the four human vesicular zinc transporters, ZnT8, supplies the millimolar zinc concentrations of insulin granules in pancreatic β-cells, affecting insulin processing, crystallisation and secretion. ZnT8 has a transmembrane and a C-terminal cytosolic domain; the latter has important functions and purportedly mediates protein-protein interactions, senses cytosolic zinc and/or channels zinc to the transport site in the transmembrane domain (TMD). A common variant W325R in the C-terminal domain (CTD) increases the risk to develop type 2 diabetes and affects autoantibody specificity in type 1 diabetes. To investigate the differences between the two protein variants, we purified and biophysically characterised both variants of the ZnT8 CTD [R325 variant of ZnT8 CTD (aa267-369) (ZnT8cR) and W325 variant of ZnT8 CTD (aa267-369) (ZnT8cW)]. The domains fold independently of the TMD. Remarkably, the ZnT8cW variant (diabetes protection in the full-length protein) is less thermostable than the ZnT8cR variant (diabetes risk in the full-length protein). The ZnT8cW monomers associate with higher affinity. Both CTD variants bind zinc with a stoichiometry that differs from bacterial homologues, emphasising the limitation of the latter as models for the structure and function of the human proteins. The relatively small but reproducible differences between the two ZnT8 CTD variants begin to provide a molecular basis for the different diabetes susceptibility caused by the full-length ZnT8 proteins.
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