Structural basis for pH-responsive amino acid transport via SLC7A4

Abstract The transport of amino acids across cell membranes is essential for metabolism, neuronal signalling, and immune system function. The amino acid polyamine organocation (APC) superfamily regulates amino acid transport through various mechanisms, including amino acid exchange, facilitative diffusion, and coupling transport to sodium or proton gradients. While many examples of mammalian APC members functioning as exchangers and sodium-coupled systems have been documented, the mechanisms underlying pH-regulated amino acid transport in mammalian cells remain unclear. Here, we report that the plasma membrane amino acid transporter SLC7A4 is regulated by low extracellular pH and functions as a leucine transporter in human cells, while also retaining the ability to bind arginine in plants. Our structural and functional data explain amino acid selectivity and pH regulation within SLC7A4, revealing an evolutionary connection to prokaryotic homologues. Molecular dynamics simulations and functional assays further reveal an allosteric mechanism for amino acid selectivity that may have broader implications for transport within the SLC7 family.