MS11-P02 The stucture of human ASCT2 neutral amino acid transporter Albert Guskov (Groningen Biomolecular Sciences and Biotechnology Institute / University of Groningen, Groningen, Netherlands (Holland, Europe)) Alisa Garaeva (Groningen Biomolecular Sciences and Biotechnology Institute / University of Groningen, Groningen, Netherlands (Holland, Europe)) Gert Oostergetel (Groningen Biomolecular Sciences and Biotechnology Institute / University of Groningen, Groningen, Netherlands (Holland, Europe)) Cornelius Gati ( Department of Structural Biology / Stanford University, Stanford, United States of America) Cristina Paulino (Groningen Biomolecular Sciences and Biotechnology Institute / University of Groningen, Groningen, Netherlands (Holland, Europe)) Dirk Slotboom (Groningen Biomolecular Sciences and Biotechnology Institute / University of Groningen, Groningen, Netherlands (Holland, Europe))email: a.guskov@rug.nlHuman ASCT2 belongs to the SLC1 family of secondary transporters and is specific for the transport of small neutral amino acids, including glutamine. ASCT2 is upregulated in cancer cells, and serves as the receptor for many retroviruses, thus it is a potential drug target. I will report a structure of human ASCT2 at 3.85 Å resolution obtained using single particle Cryo-EM. The structure of the functional and unmodified protein sheds light on the transport mechanism of SLC1 members in general, and reveals insight in specific functions of human ASCT2. ASCT2 forms a homotrimeric complex, in which each subunit contains a transport and a scaffold domain. Each of the scaffold domains contains a prominent extracellular extension, which is specific for human ASCT2 and forms the predicted docking site for retroviruses. The transporter adopts an inward-oriented state that resembles the unlocked state of a mutant of prokaryotic homologue GltPh, but in ASCT2 the transport domain is located farther towards the cytoplasmic side of the membrane where it is largely detached from the central scaffold domain. The domain detachment may be required for substrate binding and release on the intracellular side of the membrane. I will also provide a detailed comparison with the previously resolved structures of archaeal homologues of glutamate transporters Glttk and Gltph, as well as human EAAT1 transporter.References:

Keywords: glutamine transporter, ASCT2, membrane proteins