biostudies-literatureJansen RMNCI NIH HHSNIGMS NIH HHS1980-1988https://www.ebi.ac.uk/biostudies/studies/S-EPMC12477443biostudies-literatureUnknown32(10)Mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient-responsive master regulator of metabolism. Amino acids control the recruitment and activation of mTORC1 at the lysosome through the nucleotide loading state of the heterodimeric Rag GTPases. Under low nutrients, including arginine, the GTPase-activating protein complex GATOR1 promotes GTP hydrolysis on RagA/B, inactivating mTORC1. GATOR1 is regulated by the cage-like GATOR2 complex and cytosolic amino acid sensors. To understand how the arginine sensor CASTOR1 binds to GATOR2 to disinhibit GATOR1 under low cytosolic arginine, we determined the cryo-electron microscopy structure of human GATOR2 bound to CASTOR1 in the absence of arginine. Two MIOS WD40 domain β-propellers of the GATOR2 cage engage with both subunits of a singlNature structural & molecular biologyStructural basis for mTORC1 regulation by the CASTOR1-GATOR2 complex.PMC12477443R35 GM149302R01 CA285366Jansen RMRen XMaghe CHurley JHWu STapia KZoncu RYang SfalseStructural basis for mTORC1 regulation by the CASTOR1-GATOR2 complex.Mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient-responsive master regulator of metabolism. Amino acids control the recruitment and activation of mTORC1 at the lysosome through the nucleotide loading state of the heterodimeric Rag GTPases. Under low nutrients, including arginine, the GTPase-activating protein complex GATOR1 promotes GTP hydrolysis on RagA/B, inactivating mTORC1. GATOR1 is regulated by the cage-like GATOR2 complex and cytosolic amino acid sensors. To understand how the arginine sensor CASTOR1 binds to GATOR2 to disinhibit GATOR1 under low cytosolic arginine, we determined the cryo-electron microscopy structure of human GATOR2 bound to CASTOR1 in the absence of arginine. Two MIOS WD40 domain β-propellers of the GATOR2 cage engage with both subunits of a singl2025-01-01T00:00:00Z2025 Oct2026-06-11T05:06:04.516Z2026-06-11T03:08:25.022ZS-EPMC124774434071544510.1038/s41594-025-01635-0