8qrv
ASCT2 protomer in lipid nanodiscs under low Na+ concentration in the outward-facing state (OFS)
Structural highlights
FunctionAAAT_HUMAN Sodium-dependent amino acids transporter that has a broad substrate specificity, with a preference for zwitterionic amino acids. It accepts as substrates all neutral amino acids, including glutamine, asparagine, and branched-chain and aromatic amino acids, and excludes methylated, anionic, and cationic amino acids (PubMed:8702519). Through binding of the fusogenic protein syncytin-1/ERVW-1 may mediate trophoblasts syncytialization, the spontaneous fusion of their plasma membranes, an essential process in placental development (PubMed:10708449, PubMed:23492904).[1] [2] [3] (Microbial infection) Acts as a cell surface receptor for Feline endogenous virus RD114.[4] [5] (Microbial infection) Acts as a cell surface receptor for Baboon M7 endogenous virus.[6] (Microbial infection) Acts as a cell surface receptor for type D simian retroviruses.[7] Publication Abstract from PubMedASCT2 is an obligate exchanger of neutral amino acids, contributing to cellular amino acid homeostasis. ASCT2 belongs to the same family (SLC1) as Excitatory Amino Acid Transporters (EAATs) that concentrate glutamate in the cytosol. The mechanism that makes ASCT2 an exchanger rather than a concentrator remains enigmatic. Here, we employ cryo-electron microscopy and molecular dynamics simulations to elucidate the structural basis of the exchange mechanism of ASCT2. We establish that ASCT2 binds three Na(+) ions per transported substrate and visits a state that likely acts as checkpoint in preventing Na(+) ion leakage, both features shared with EAATs. However, in contrast to EAATs, ASCT2 retains one Na(+) ion even under Na(+)-depleted conditions. We demonstrate that ASCT2 cannot undergo the structural transition in TM7 that is essential for the concentrative transport cycle of EAATs. This structural rigidity and the high-affinity Na(+) binding site effectively confine ASCT2 to an exchange mode. Structural basis of the obligatory exchange mode of human neutral amino acid transporter ASCT2.,Borowska AM, Chiariello MG, Garaeva AA, Rheinberger J, Marrink SJ, Paulino C, Slotboom DJ Nat Commun. 2024 Aug 3;15(1):6570. doi: 10.1038/s41467-024-50888-8. PMID:39095408[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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