Structure and mechanism of human vesicular polyamine transporter.

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⁺ compet

SUBMITTER: Guo Y 

PROVIDER: S-EPMC12049414 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature