Structure and mechanisms of transport of human Asc1/CD98hc amino acid transporter

Josep Rullo-Tubau, Maria Martinez-Molledo, Paola Bartoccioni, Ignasi Puch-Giner, Ángela Arias, Suwipa Saen-Oon, Camille Stephan-Otto Attolini, Rafael Artuch, Lucía Díaz, Víctor Guallar, Ekaitz Errasti-Murugarren (), Manuel Palacín () and Oscar Llorca ()
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Josep Rullo-Tubau: The Barcelona Institute of Science and Technology (BIST)
Maria Martinez-Molledo: Spanish National Cancer Research Centre (CNIO)
Paola Bartoccioni: The Barcelona Institute of Science and Technology (BIST)
Ignasi Puch-Giner: Barcelona Supercomputing Center
Ángela Arias: Sant Joan de Déu Research Institute
Suwipa Saen-Oon: Nostrum Biodiscovery
Camille Stephan-Otto Attolini: The Barcelona Institute of Science and Technology (BIST)
Rafael Artuch: The Spanish Center of Rare Diseases (CIBERER U-731)
Lucía Díaz: Nostrum Biodiscovery
Víctor Guallar: Barcelona Supercomputing Center
Ekaitz Errasti-Murugarren: The Spanish Center of Rare Diseases (CIBERER U-731)
Manuel Palacín: The Barcelona Institute of Science and Technology (BIST)
Oscar Llorca: Spanish National Cancer Research Centre (CNIO)

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Recent cryoEM studies elucidated details of the structural basis for the substrate selectivity and translocation of heteromeric amino acid transporters. However, Asc1/CD98hc is the only neutral heteromeric amino acid transporter that can function through facilitated diffusion, and the only one that efficiently transports glycine and D-serine, and thus has a regulatory role in the central nervous system. Here we use cryoEM, ligand-binding simulations, mutagenesis, transport assays, and molecular dynamics to define human Asc1/CD98hc determinants for substrate specificity and gain insights into the mechanisms that govern substrate translocation by exchange and facilitated diffusion. The cryoEM structure of Asc1/CD98hc is determined at 3.4–3.8 Å resolution, revealing an inward-facing semi-occluded conformation. We find that Ser 246 and Tyr 333 are essential for Asc1/CD98hc substrate selectivity and for the exchange and facilitated diffusion modes of transport. Taken together, these results reveal the structural bases for ligand binding and transport features specific to human Asc1.

Date: 2024
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DOI: 10.1038/s41467-024-47385-3

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