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Engineering of a mammalian VMAT2 for cryo-EM analysis results in non-canonical protein folding

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  • Ying Lyu

    (Sichuan University)

  • Chunting Fu

    (Sichuan University)

  • Haiyun Ma

    (Sichuan University)

  • Zhaoming Su

    (Sichuan University)

  • Ziyi Sun

    (Sichuan University)

  • Xiaoming Zhou

    (Sichuan University)

Abstract

Vesicular monoamine transporter 2 (VMAT2) belongs to the major facilitator superfamily (MFS), and mediates cytoplasmic monoamine packaging into presynaptic vesicles. Here, we present two cryo-EM structures of VMAT2, with a frog VMAT2 adopting a canonical MFS fold and an engineered sheep VMAT2 adopting a non-canonical fold. Both VMAT2 proteins mediate uptake of a selective fluorescent VMAT2 substrate into cells. Molecular docking, substrate binding and transport analysis reveal potential substrate binding mechanism in VMAT2. Meanwhile, caution is advised when interpreting engineered membrane protein structures.

Suggested Citation

  • Ying Lyu & Chunting Fu & Haiyun Ma & Zhaoming Su & Ziyi Sun & Xiaoming Zhou, 2024. "Engineering of a mammalian VMAT2 for cryo-EM analysis results in non-canonical protein folding," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50934-5
    DOI: 10.1038/s41467-024-50934-5
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    1. Feiwen Wei & Huihui Liu & Wei Zhang & Jufang Wang & Yanqing Zhang, 2025. "Drug inhibition and substrate transport mechanisms of human VMAT2," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    2. Pujun Xie & Yan Li & Gaëlle Lamon & Huihui Kuang & Da-Neng Wang & Nathaniel J. Traaseth, 2025. "A fiducial-assisted strategy compatible with resolving small MFS transporter structures in multiple conformations using cryo-EM," Nature Communications, Nature, vol. 16(1), pages 1-17, December.

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