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Structural insights of ZIP4 extracellular domain critical for optimal zinc transport

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  • Tuo Zhang

    (Michigan State University)

  • Dexin Sui

    (Michigan State University)

  • Jian Hu

    (Michigan State University
    Michigan State University)

Abstract

The ZIP zinc transporter family is responsible for zinc uptake from the extracellular milieu or intracellular vesicles. The LIV-1 subfamily, containing nine out of the 14 human ZIP proteins, is featured with a large extracellular domain (ECD). The critical role of the ECD is manifested by disease-causing mutations on ZIP4, a representative LIV-1 protein. Here we report the first crystal structure of a mammalian ZIP4-ECD, which reveals two structurally independent subdomains and an unprecedented dimer centred at the signature PAL motif. Structure-guided mutagenesis, cell-based zinc uptake assays and mapping of the disease-causing mutations indicate that the two subdomains play pivotal but distinct roles and that the bridging region connecting them is particularly important for ZIP4 function. These findings lead to working hypotheses on how ZIP4-ECD exerts critical functions in zinc transport. The conserved dimeric architecture in ZIP4-ECD is also demonstrated to be a common structural feature among the LIV-1 proteins.

Suggested Citation

  • Tuo Zhang & Dexin Sui & Jian Hu, 2016. "Structural insights of ZIP4 extracellular domain critical for optimal zinc transport," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11979
    DOI: 10.1038/ncomms11979
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    Cited by:

    1. Yao Zhang & Majid Jafari & Tuo Zhang & Dexin Sui & Luca Sagresti & Kenneth M. Merz & Jian Hu, 2024. "Molecular insights into substrate translocation in an elevator-type metal transporter," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Basavraj Khanppnavar & Julian Maier & Freja Herborg & Ralph Gradisch & Erika Lazzarin & Dino Luethi & Jae-Won Yang & Chao Qi & Marion Holy & Kathrin Jäntsch & Oliver Kudlacek & Klaus Schicker & Thomas, 2022. "Structural basis of organic cation transporter-3 inhibition," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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