9SP8

Cryo-EM structure of the Arabidopsis thaliana CAT4 transporter in the outward-open L-ornithine bound state

Summary for 9SP8

• Entry DOI: 10.2210/pdb9sp8/pdb
• EMDB information: 55065
• Descriptor: SybB5, Cationic amino acid transporter 4, vacuolar, L-ornithine, ... (7 entities in total)
• Functional Keywords: membrane transporter, cationic amino acid, transport protein
• Biological source: synthetic construct; More
• Total number of polymer chains: 2
• Total formula weight: 79618.97

Authors

Kolokouris, D.,Newstead, S. (deposition date: 2025-09-16, release date: 2026-09-30)

Primary citation

Kolokouris, D.,Bothra, A.,Kato, T.,Zeng, Y.C.,Lichtinger, S.,Parker, J.L.,Biggin, P.C.,Newstead, S.
Structural basis for pH-responsive amino acid transport via SLC7A4.
Nat Commun, 17:-, 2026

PubMed 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 controls amino acid transport via mechanisms including amino acid exchange, facilitative diffusion, and sodium- or proton-coupled transport. Although many mammalian APC members functioning as exchangers and sodium-coupled systems have been identified, the mechanisms underlying pH-regulated amino acid transport in mammalian cells remain unclear. Here, we show that the plasma membrane amino acid transporter SLC7A4 is regulated by low extracellular pH and functions as a leucine transporter in human cells. Using Cryo-EM structures of the plant homologue, CAT4, from Arabidopsis thaliana in outward-open apo and L-ornithine-bound states, as well as transport assays and molecular dynamics simulations based on homology models of the human transporter, we identify residues responsible for amino acid selectivity that supports an allosteric mechanism linking ligand recognition to pH regulation. This mechanism is consistent with an evolutionary link to proton-coupled prokaryotic homologues. Overall, our findings provide a structural and functional basis for pH-gated leucine transport by the human SLC7A4 transporter and provides a framework for understanding amino acid selectivity within the wider SLC7 family.

PubMed: 41904136
DOI: 10.1038/s41467-026-70956-5

Experimental method

ELECTRON MICROSCOPY (3.32 Å)