Structure and mechanism of human vesicular polyamine transporter

Yi Guo, Ge Yang, Haijiao Liu, Jin Chai, Jie Chen, John Shanklin, Qun Liu (), Bin Liu () and Min Lu ()
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Yi Guo: Rosalind Franklin University of Medicine & Science
Ge Yang: University of Minnesota
Haijiao Liu: Brookhaven National Laboratory
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

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59549-w

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