Cryo-EM structures of human PAT1 (SLC36A1) in apo and substrate-bound states reveal a convergent binding mode for diverse zwitterionic amino acids; PAT1 mediates lysosomal amino acid export and mTORC1 activation.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Recombinant human protein (cryo-EM) |
| Journal | Nature Communications |
| Year | 2026 |
| Peer reviewed | Yes |
| Source | DOI 10.1038/s41467-026-75306-z · PMID 42414312 |
The proton-coupled amino-acid transporter SLC36A1 (hPAT1) is an atypical H+-driven carrier and mediates the intestinal absorption of a wide array of zwitterionic amino-acid analogs, including many compounds with central nervous-system (CNS) activity, as well as the activation of the mTORC1 pathway and the export of amino acids from lysosomes, thereby maintaining cellular amino-acid homeostasis. Here, we present the cryo-EM structures of a member of the SLC36 family, hPAT1, in its apo state and in complex with three chemically distinct substrates, including the alpha-amino acid D-serine, the beta-amino acid nipecotic acid, and the heterocyclic drug D-cycloserine, at resolutions of 3.4-3.5 A. Despite their chemical diversity, all ligands adopt a spatially convergent binding mode, elucidating the structural basis for PAT1's broad substrate promiscuity. In addition, we identify E270 as a potential proton-binding site. Together, these findings provide structural insights into the molecular mechanism of proton-coupled amino acid transport.
| Intervention | Structural/biochemical (cryo-EM of SLC36A1/PAT1, apo + 3 substrate-bound states) |
| Target | SLC36A1 (PAT1) / lysosomal amino acid efflux / mTORC1 activation |
| Model | Human (recombinant protein, cryo-EM; no animal/cell phenotype data) |
| Effect | Reveals structural basis for substrate promiscuity of PAT1; supports PAT1's role in lysosomal amino acid export and mTORC1 activation |