Substrate recognition and ion coupling mechanism of the human VIAAT
- 1Institute of Biophysics, Chinese Academy of Sciences
Abstract
Inhibitory neurotransmission, essential for neural circuit homeostasis and proper neurological function, depends on the efficient sequestration of {gamma}-aminobutyric acid (GABA) and glycine into synaptic vesicles. This critical process is mediated exclusively by the vesicular inhibitory amino acid transporter (VIAAT). Despite extensive biochemical and physiological investigation, the molecular mechanism governing VIAAT-mediated transport has remained incompletely understood. Here, we determined structures of human VIAAT in multiple functional states, including apo, GABA-bound, and glycine-bound states, as well as apo state in chloride-free condition. VIAAT adopts a classical LeuT-fold and we elucidated how its large, electronegative binding pocket accommodates both GABA and glycine. Moreover, we resolved two previously unidentified chloride-binding sites. Through integrative molecular dynamics simulations and functional mutagenesis, our results support roles for chloride and the conserved residue E213 in substrate binding and proton-coupled transport. Together, our findings establish a structural framework for VIAAT-mediated inhibitory neurotransmitter transport that illuminates the molecular basis of inhibitory synaptic transmission and provides a foundation for understanding VIAAT dysfunction in epilepsy and related neurodevelopmental disorders.
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BibTeX
@misc{wei2026substrate,
title = {{Substrate recognition and ion coupling mechanism of the human VIAAT}},
author = {Y. Wei and K. Ma and K. Hao and Q. Bai and J. Zhao and X. Xie and R. Li and Q. Chen and Y. Li and H. Zhang and Z. Cao and T. Hu and Y. Zhao},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.12.751155},
url = {https://www.biorxiv.org/content/10.64898/2026.09.12.751155v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Substrate recognition and ion coupling mechanism of the human VIAAT
AU - Y. Wei
AU - K. Ma
AU - K. Hao
AU - Q. Bai
AU - J. Zhao
AU - X. Xie
AU - R. Li
AU - Q. Chen
AU - Y. Li
AU - H. Zhang
AU - Z. Cao
AU - T. Hu
AU - Y. Zhao
PY - 2026
DA - 2026/09/12
PB - bioRxiv
DO - 10.64898/2026.09.12.751155
UR - https://www.biorxiv.org/content/10.64898/2026.09.12.751155v1
AB - Inhibitory neurotransmission, essential for neural circuit homeostasis and proper neurological function, depends on the efficient sequestration of {gamma}-aminobutyric acid (GABA) and glycine into synaptic vesicles. This critical process is mediated exclusively by the vesicular inhibitory amino acid transporter (VIAAT). Despite extensive biochemical and physiological investigation, the molecular mechanism governing VIAAT-mediated transport has remained incompletely understood. Here, we determined structures of human VIAAT in multiple functional states, including apo, GABA-bound, and glycine-bound states, as well as apo state in chloride-free condition. VIAAT adopts a classical LeuT-fold and we elucidated how its large, electronegative binding pocket accommodates both GABA and glycine. Moreover, we resolved two previously unidentified chloride-binding sites. Through integrative molecular dynamics simulations and functional mutagenesis, our results support roles for chloride and the conserved residue E213 in substrate binding and proton-coupled transport. Together, our findings establish a structural framework for VIAAT-mediated inhibitory neurotransmitter transport that illuminates the molecular basis of inhibitory synaptic transmission and provides a foundation for understanding VIAAT dysfunction in epilepsy and related neurodevelopmental disorders.
ER -