Structural basis of augment taurine uptake by taurine transporter alleviating cellular senescence

Abstract

Taurine, a sulfur-containing amino acid, is critical for diverse physiological processes including liver function, cardiovascular health, and neurological development. Its deficiency has been linked to liver damage, cardiomyopathy, retinal degeneration, and accelerated aging. Despite its importance in metabolic regulation and disease prevention, the structural basis for taurines cellular uptake and its potential therapeutic applications have remained elusive. Here, we present high-resolution cryo-electron microscopy structures of the human taurine transporter (TauT) in multiple conformational states, revealing key insights into the taurine transport mechanism. We identify five distinct taurine-binding sites, elucidating a continuous pathway for taurine translocation across the cell membrane. Notably, we discover a novel gating mechanism involving a conserved salt bridge, which when disrupted, significantly enhances taurine uptake. Leveraging these structural insights, we demonstrate that augmented taurine uptake via TauT alleviates stress-induced senescence in biliary epithelial cells, potentially through the upregulation of the stress-responsive gene ATF3. Our findings not only advance the understanding of neurotransmitter transport but also unveil TauT as a promising therapeutic target for age-related liver diseases and other senescence-associated disorders. This work bridges structural biology with physiological function, offering new avenues for developing interventions to combat cellular aging and taurine-deficiency related diseases.