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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/214174
Structure and mechanisms of transport of human Asc1/CD98hc amino acid transporter
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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 angstrom 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. Asc1/CD98hc is a key regulator of small neutral amino acid transport in the brain and adipose tissue. Here, authors report the structure of semi-occluded hAsc1/CD98hc and provide a model for Asc1 exchange and facilitated diffusion modes of transport.
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RULLO TUBAU, Josep, MARTÍNEZ MOLLEDO, Maria, BARTOCCIONI, Paola, PUCH GINER, Ignasi, ARIAS, Ángela, SAEN-OON, Suwipa, STEPHAN-OTTO ATTOLINI, Camille, ARTUCH, Rafael, DÍAZ, Lucía, GUALLAR, Victor, ERRASTI-MURUGARREN, Ekaitz, PALACÍN, Manuel, LLORCA, Oscar. Structure and mechanisms of transport of human Asc1/CD98hc amino acid transporter. _Nature Communications_. 2024. Vol. 15, núm. 1. [consulta: 9 de gener de 2026]. ISSN: 2041-1723. [Disponible a: https://hdl.handle.net/2445/214174]