6NZD
Cryo-EM Structure of the Lysosomal Folliculin Complex (FLCN-FNIP2-RagA-RagC-Ragulator)
Summary for 6NZD
| Entry DOI | 10.2210/pdb6nzd/pdb |
| EMDB information | 0554 0556 |
| Descriptor | Ragulator complex protein LAMTOR1, GUANOSINE-5'-DIPHOSPHATE, 9-{5-O-[(S)-hydroxy{[(R)-hydroxy(thiophosphonooxy)phosphoryl]oxy}phosphoryl]-alpha-L-arabinofuranosyl}-3,9-dihydro-1H-purine-2,6-dione, ... (11 entities in total) |
| Functional Keywords | lysosome, mtorc1 regulation, amino acid sensing, gtpase, signaling protein, signaling protein-inhibitor complex, signaling protein/inhibitor |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 9 |
| Total formula weight | 348515.78 |
| Authors | Fromm, S.A.,Young, L.N.,Hurley, J.H. (deposition date: 2019-02-13, release date: 2019-11-06, Last modification date: 2024-11-20) |
| Primary citation | Lawrence, R.E.,Fromm, S.A.,Fu, Y.,Yokom, A.L.,Kim, D.J.,Thelen, A.M.,Young, L.N.,Lim, C.Y.,Samelson, A.J.,Hurley, J.H.,Zoncu, R. Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex. Science, 366:971-977, 2019 Cited by PubMed Abstract: The tumor suppressor folliculin (FLCN) enables nutrient-dependent activation of the mechanistic target of rapamycin complex 1 (mTORC1) protein kinase via its guanosine triphosphatase (GTPase) activating protein (GAP) activity toward the GTPase RagC. Concomitant with mTORC1 inactivation by starvation, FLCN relocalizes from the cytosol to lysosomes. To determine the lysosomal function of FLCN, we reconstituted the human lysosomal FLCN complex (LFC) containing FLCN, its partner FLCN-interacting protein 2 (FNIP2), and the RagA:RagC GTPases as they exist in the starved state with their lysosomal anchor Ragulator complex and determined its cryo-electron microscopy structure to 3.6 angstroms. The RagC-GAP activity of FLCN was inhibited within the LFC, owing to displacement of a catalytically required arginine in FLCN from the RagC nucleotide. Disassembly of the LFC and release of the RagC-GAP activity of FLCN enabled mTORC1-dependent regulation of the master regulator of lysosomal biogenesis, transcription factor E3, implicating the LFC as a checkpoint in mTORC1 signaling. PubMed: 31672913DOI: 10.1126/science.aax0364 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.6 Å) |
Structure validation
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