Biology subjects

Maret, W.

Publications and source records attributed to Maret, W..

3 recordsLinked to original sources

bioRxiv2025

Structures and zinc ion transport pathways of the human SLC39A family of metal transporters

The SLC39A (ZIP) family of zinc ion transporters play a pivotal role in maintaining zinc homeostasis, which is essential for numerous physiological processes involving enzyme catalysis, protein structure and regulation in signal transduction. This investigation employed AlphaFold3 to predict and analyze the 3D structures of all 14 human ZIP family members and revealed key structural and functional features, including transmembrane domains with eight alpha-helices, extracellular and cytoplasmic domains, dimerization, and zinc ion transport pathways. Unique zinc-binding motifs--composed of histidine, aspartic acid, and glutamic acid--were identified. They facilitate zinc ion attraction, selection, and transport. The findings highlight significant structural diversity in these proteins, with additional alpha-helices, disulfide bonds, and other conserved motifs that together contribute to functional specialization across the ZIP family members. Compared to predictions, which exist only for ZIP4, the models incorporate dimeric structures, rationalize loop conformations, and achieve a higher resolution. The predicted 3D structures offer enhanced insights into zinc ion transport mechanisms and provide a foundation for future research into the structural biology of these proteins and their interacting partners in physiology and pathology.

biochemistry↗

bioRxiv2024

The KDM6 histone demethylase inhibitor GSK-J4 induces metal and stress responses in multiple myeloma cells

Thioneins are cysteine-rich apoproteins that regulate divalent metal homeostasis by virtue of their metal-chelation properties resulting in the ligand-bound metallothionein state. Previous studies show transient upregulation of the metallothionein (MT) gene cluster as part of a complex transcriptional response to a class of histone demethylase tool compounds targeting human Fe2+ dependent ketoglutarate oxygenases KDM6A (UTX) and KDM6B (JmjD3). The prototypic bioactive KDM6 inhibitor GSK-J4 induces apoptotic cell death in multiple myeloma cells and corresponding transcriptomic profiles are dominated by metal and metabolic stress response signatures, also observed in primary human myeloma cells. Here we investigate the hypothesis that metal-chelation by GSK-J4 provides the means for transport and intracellular release of Zn2+ leading to a metallothionein transcriptomic response signature. Live cell imaging of myeloma cells shows transient increases in intracellular free Zn2+ concentrations when exposed to GSK-J4, consistent with a model of inhibitor-mediated metal transport. Comparisons of GSK-J4 and ZnSO4 treatments in the presence or absence of metal chelators show that both treatment conditions induce different transcription factor repertoires with an overlapping MTF1 transcriptional regulation responsible for metallothionein and metal ion transport regulation. The data provide a possible explanation for the observed metal response upon GSK-J4 inhibition however the relationship with the pro-apoptotic mechanism in myeloma cells requires further investigation.

cell biology↗

bioRxiv2022

Aryl hydrocarbon receptor utilises cellular zinc signals to maintain the gut epithelial barrier

Both zinc and plant-derived ligands of the aryl hydrocarbon receptor (AHR) are dietary components which regulate intestinal epithelial barrier function and protect against Inflammatory Bowel Disease (IBD)1,2. Here, we explore whether zinc and AHR pathway are linked using a mouse IBD model with follow-on studies on human and mouse ileum organoids. Our data demonstrate that AHR regulates cellular zinc uptake, and that zinc is an integral part of AHR signalling processes. We show that dietary supplementation in mice with the plant-derived AHR ligand precursor, indole-3-carbinol (I3C), offers a high level of protection against dextran sulfate sodium induced IBD while protection fails in mice with AHR deleted in the intestinal epithelium. AHR agonist treatment is also ineffective in mice with a nutritional zinc deficiency. Experiments in the human Caco-2 cell line and ileum organoids showed that AHR activation increases total cellular zinc and cytosolic free Zn2+ concentrations through transcriptional upregulation of several SLC39 zinc importers. As a consequence, genes for tight junction (TJ) proteins were upregulated in a zinc-dependent manner involving zinc inhibition of signalling to NF-{kappa}B and attenuated degradation of TJ proteins through zinc inhibition of calpain activity. Thus, our data indicate that AHR activation by plant-derived dietary ligands improves gut barrier function via zinc-dependent cellular pathways, suggesting that combined dietary supplementation with AHR ligands and zinc might be effective in preventing and treating inflammatory gut disorders.

cell biology↗