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Structure and mechanism of human vesicular polyamine transporter

Author

Listed:
  • Yi Guo

    (Rosalind Franklin University of Medicine & Science)

  • Ge Yang

    (University of Minnesota)

  • Haijiao Liu

    (Brookhaven National Laboratory
    Stony Brook University)

  • Jin Chai

    (Brookhaven National Laboratory)

  • Jie Chen

    (University of Minnesota)

  • John Shanklin

    (Brookhaven National Laboratory)

  • Qun Liu

    (Brookhaven National Laboratory)

  • Bin Liu

    (University of Minnesota)

  • Min Lu

    (Rosalind Franklin University of Medicine & Science)

Abstract

Polyamines play essential roles in gene expression and modulate neuronal transmission in mammals. Vesicular polyamine transporters (VPAT) from the SLC18 family exploit the transmembrane H+ gradient to translocate polyamines into secretory vesicles, enabling the quantal release of polyamine neuromodulators and underpinning learning and memory formation. Here, we report the cryo-electron microscopy structures of human VPAT in complex with spermine, spermidine, H+, or tetrabenazine, elucidating discrete lumen-facing states of the antiporter and pivotal interactions between VPAT and its substrate or inhibitor. Leveraging structure-inspired mutagenesis studies and protein structure prediction, we deduce an unforeseen mechanism whereby the polyamine and H+ compete for multiple acidic protein residues both directly and indirectly, and rationalize how the antidopaminergic therapeutic tetrabenazine impedes vesicular transport of polyamines. This study unravels the mechanism of an H+-coupled polyamine antiporter, reveals mechanistic diversity between VPAT and other SLC18 antiporters, and raises new prospects for combating human disorders of polyamine homeostasis.

Suggested Citation

  • Yi Guo & Ge Yang & Haijiao Liu & Jin Chai & Jie Chen & John Shanklin & Qun Liu & Bin Liu & Min Lu, 2025. "Structure and mechanism of human vesicular polyamine transporter," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59549-w
    DOI: 10.1038/s41467-025-59549-w
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