2026-04-17T12:06:21Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/2141742025-12-05T12:09:15Zcom_2072_1057col_2072_478799col_2072_478916col_2072_478917

00925njm 22002777a 4500 dc Rullo Tubau, Josep author Martínez Molledo, Maria author Bartoccioni, Paola author Puch Giner, Ignasi author Arias, Ángela author Saen-oon, Suwipa author Stephan-Otto Attolini, Camille author Artuch, Rafael author Díaz, Lucía author Guallar, Victor author Errasti-Murugarren, Ekaitz author Palacín, Manuel author Llorca, Oscar author 2024-07-02T15:28:56Z 2024-07-02T15:28:56Z 2024-04-06 2024-06-17T13:53:03Z 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. Aminoàcids Enginyeria de proteïnes Amino acids Protein engineering Structure and mechanisms of transport of human Asc1/CD98hc amino acid transporter