Researchers at IRB Barcelona discover a molecular ‘switch’ that regulates amino acid entry into cells

LAT amino acid transporters are essential proteins for cell metabolism and they are involved in various rare diseases and metabolic disorders. A study published in the journal PNAS Nexus by Dr. Joana Fort and Prof. Manuel Palacín, in collaboration with the group led by Prof. Thorben Cordes at the University of Munich (LMU) and involving the participation of the teams headed by Prof. Modesto Orozco (IRB Barcelona) and Dr. Óscar Llorca (CNIO), has shed light on the mechanism used by these amino acid transporters. 

Notably, the research reveals that an amino acid called lysine, located in a specific region of the protein (transmembrane helix 5), acts like a spring to regulate the opening and closing of the inner gate of these transporters. This mechanism ensures precise control over amino acid passage across the cell membrane, much like how a spring in the main entrance door of a building guarantees proper opening and closing.

Using a multidisciplinary approach that combined cryo-electron microscopy (cryo-EM), single-molecule Förster resonance energy transfer (smFRET), and molecular dynamics simulations, the team has characterized the key interaction between the conserved lysine in transmembrane helix 5 of the BasC transporter. They have observed that this lysine stabilizes the conformational changes needed for the protein to undertake amino acid exchange, a key process for many cell functions.

“Thanks to the combination of cutting-edge experimental techniques, we have been able to 'observe' and precisely quantify these molecular movements,” says Dr. Fort, a researcher at IRB Barcelona and CIBERER and co-first and co-corresponding author of the paper. This study is the fruit of joint research undertaken with Dr. Adrià Nicolàs and other scientists at IRB Barcelona, LMU and CNIO, whose efforts have been instrumental in unravelling the role of lysine in regulating the inner gate of LAT transporters.

“Our results show how the lysine residue plays a key role in regulating the inner gate of these transporters and they pave the way for a deeper understanding of its amino acid transport function and its connections to several pathologies,” explains Prof. Palacín, head of the Amino Acid Transporters and Disease laboratory at IRB Barcelona and professor in the Department of Biochemistry and Molecular Biomedicine at the Faculty of Biology, UB, and group leader at CIBERER. “It is worth noting that this lysine is mutated in the y+LAT1 transporter in human patients with Lysinuric Protein Intolerance (LPI), thus highlighting its key role in the function of these transporters.”

The findings of this study provide new insights for the potential development of therapeutic strategies aimed at modulating the activity of amino acid transporters, with potential applications in conditions such as metabolic disorders, rare diseases, and cancer.

Related article:
The conserved lysine residue in transmembrane helix 5 is pivotal for the cytoplasmic gating of the L-amino acid transporters
Joana Fort, Adrià Nicolàs-Aragó, Luca Maggi, Maria Martinez-Molledo, Despoina Kapiki, Paula González-Novoa, Patricia Gómez-Gejo, Niels Zijlstra, Susanna Bodoy, Els Pardon, Jan Steyaert, Oscar Llorca, Modesto Orozco, Thorben Cordes, Manuel Palacín
PNAS nexus (2025) DOI: 10.1093/pnasnexus/pgae584