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Cryo-EM structures of human zinc transporter ZnT7 reveal the mechanism of Zn2+ uptake into the Golgi apparatus

Author

Listed:
  • Han Ba Bui

    (Tohoku University
    Tohoku University)

  • Satoshi Watanabe

    (Tohoku University
    Tohoku University
    Tohoku University)

  • Norimichi Nomura

    (Kyoto University)

  • Kehong Liu

    (Kyoto University)

  • Tomoko Uemura

    (Kyoto University)

  • Michio Inoue

    (Tohoku University)

  • Akihisa Tsutsumi

    (The University of Tokyo)

  • Hiroyuki Fujita

    (Canon Medical Systems Corporation)

  • Kengo Kinoshita

    (Tohoku University
    Tohoku University)

  • Yukinari Kato

    (Tohoku University)

  • So Iwata

    (Kyoto University)

  • Masahide Kikkawa

    (The University of Tokyo)

  • Kenji Inaba

    (Tohoku University
    Tohoku University
    Tohoku University
    Kyushu University)

Abstract

Zinc ions (Zn2+) are vital to most cells, with the intracellular concentrations of Zn2+ being tightly regulated by multiple zinc transporters located at the plasma and organelle membranes. We herein present the 2.2-3.1 Å-resolution cryo-EM structures of a Golgi-localized human Zn2+/H+ antiporter ZnT7 (hZnT7) in Zn2+-bound and unbound forms. Cryo-EM analyses show that hZnT7 exists as a dimer via tight interactions in both the cytosolic and transmembrane (TM) domains of two protomers, each of which contains a single Zn2+-binding site in its TM domain. hZnT7 undergoes a TM-helix rearrangement to create a negatively charged cytosolic cavity for Zn2+ entry in the inward-facing conformation and widens the luminal cavity for Zn2+ release in the outward-facing conformation. An exceptionally long cytosolic histidine-rich loop characteristic of hZnT7 binds two Zn2+ ions, seemingly facilitating Zn2+ recruitment to the TM metal transport pathway. These structures permit mechanisms of hZnT7-mediated Zn2+ uptake into the Golgi to be proposed.

Suggested Citation

  • Han Ba Bui & Satoshi Watanabe & Norimichi Nomura & Kehong Liu & Tomoko Uemura & Michio Inoue & Akihisa Tsutsumi & Hiroyuki Fujita & Kengo Kinoshita & Yukinari Kato & So Iwata & Masahide Kikkawa & Kenj, 2023. "Cryo-EM structures of human zinc transporter ZnT7 reveal the mechanism of Zn2+ uptake into the Golgi apparatus," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40521-5
    DOI: 10.1038/s41467-023-40521-5
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    1. Yoshiki Tanaka & Christopher J. Hipolito & Andrés D. Maturana & Koichi Ito & Teruo Kuroda & Takashi Higuchi & Takayuki Katoh & Hideaki E. Kato & Motoyuki Hattori & Kaoru Kumazaki & Tomoya Tsukazaki & , 2013. "Structural basis for the drug extrusion mechanism by a MATE multidrug transporter," Nature, Nature, vol. 496(7444), pages 247-251, April.
    2. Yuta Amagai & Momo Yamada & Toshiyuki Kowada & Tomomi Watanabe & Yuyin Du & Rong Liu & Satoshi Naramoto & Satoshi Watanabe & Junko Kyozuka & Tiziana Anelli & Tiziana Tempio & Roberto Sitia & Shin Mizu, 2023. "Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Hirotake Miyauchi & Satomi Moriyama & Tsukasa Kusakizako & Kaoru Kumazaki & Takanori Nakane & Keitaro Yamashita & Kunio Hirata & Naoshi Dohmae & Tomohiro Nishizawa & Koichi Ito & Takaaki Miyaji & Yosh, 2017. "Structural basis for xenobiotic extrusion by eukaryotic MATE transporter," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
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