6NZD

Cryo-EM Structure of the Lysosomal Folliculin Complex (FLCN-FNIP2-RagA-RagC-Ragulator)

6NZD の概要

• エントリーDOI: 10.2210/pdb6nzd/pdb
• EMDBエントリー: 0554 0556
• 分子名称: 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)
• 機能のキーワード: lysosome, mtorc1 regulation, amino acid sensing, gtpase, signaling protein, signaling protein-inhibitor complex, signaling protein/inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 348515.78

構造登録者

Fromm, S.A.,Young, L.N.,Hurley, J.H. (登録日: 2019-02-13, 公開日: 2019-11-06, 最終更新日: 2019-12-18)

主引用文献

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

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: 31672913
DOI: 10.1126/science.aax0364

実験手法

ELECTRON MICROSCOPY (3.6 Å)