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

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.

HATs meet structural biology.

Heteromeric amino acid transporters (HATs) are one of the ten types of amino acid transporters present in the human body. Growing interest in the pathophysiological role of this group of transporters in rare and complex diseases and cancer has brought about the recent resolution of various structures of human HATs and bacterial homologues at atomic level. This knowledge sheds light on the mechanisms of transport used by these molecules. Here, we discuss the molecular bases underlying substrate specificity, binding asymmetry, and the impact of disease-causing mutations on transporter biogenesis and function.