biostudies-literatureUnknown11(12)Dai LHeteromeric amino acid transporters (HATs), including y⁺LAT1-4F2hc complex, are responsible for transporting amino acids across membranes, and mutations in y⁺LAT1 cause lysinuric protein intolerance (LPI), a hereditary disorder characterized by defective cationic amino acid transport. The relationship between LPI and specific mutations in y⁺LAT1 has yet to be fully understood. In this study, we characterized the function of y⁺LAT1-4F2hc complex in mammalian cells and determined the cryo-EM structures of the human y⁺LAT1-4F2hc complex in two distinct conformations: the apo state in an inward-open conformation and the native substrate-bound state in an outward-open conformation. Structural analysis suggests that Asp²⁴³ in y<suScience advanceseadq0558https://www.ebi.ac.uk/biostudies/studies/S-EPMC11922002biostudies-literatureStructural basis for the substrate recognition and transport mechanism of the human y&lt;sup&gt;+&lt;/sup&gt;LAT1-4F2hc transporter complex.PMC11922002Xu KLi YDai LZeng QZhang TZhou QHuang JZhang YYan RWang ZShi YfalseStructural basis for the substrate recognition and transport mechanism of the human y&lt;sup&gt;+&lt;/sup&gt;LAT1-4F2hc transporter complex.Heteromeric amino acid transporters (HATs), including y⁺LAT1-4F2hc complex, are responsible for transporting amino acids across membranes, and mutations in y⁺LAT1 cause lysinuric protein intolerance (LPI), a hereditary disorder characterized by defective cationic amino acid transport. The relationship between LPI and specific mutations in y⁺LAT1 has yet to be fully understood. In this study, we characterized the function of y⁺LAT1-4F2hc complex in mammalian cells and determined the cryo-EM structures of the human y⁺LAT1-4F2hc complex in two distinct conformations: the apo state in an inward-open conformation and the native substrate-bound state in an outward-open conformation. Structural analysis suggests that Asp²⁴³ in y<su2025-01-01T00:00:00Z2025 Mar2026-06-03T02:32:53.748Z2025-04-04T00:32:05.658ZS-EPMC119220024010654510.1126/sciadv.adq0558