Structure and mechanism of human vesicular polyamine transporter

Guo, Yi; Yang, Ge; Liu, Haijiao; Chai, Jin; Chen, Jie; Shanklin, John; Liu, Qun; Liu, Bin; Lu, Min

doi:10.1038/s41467-025-59549-w

Structure and mechanism of human vesicular polyamine transporter

Journal Article · Sat May 03 00:00:00 EDT 2025 · Nature Communications

DOI:https://doi.org/10.1038/s41467-025-59549-w· OSTI ID:2566968

Guo, Yi ^[1]; Yang, Ge ^[2]; Liu, Haijiao ^[3]; ^[3]; Chen, Jie ^[2]; ^[3]; ^[3]; ^[2]; ^[1]

Rosalind Franklin University of Medicine and Science, Chicago, IL (United States)
Univ. of Minnesota, Austin, MN (United States). Hormel Inst.
Brookhaven National Laboratory (BNL), Upton, NY (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)

Grant/Contract Number:: SC0012704

OSTI ID:: 2566968

Report Number(s):: BNL--228171-2025-JAAM

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 16; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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