6CES

Cryo-EM structure of GATOR1-RAG

6CES の概要

• エントリーDOI: 10.2210/pdb6ces/pdb
• EMDBエントリー: 7464
• 分子名称: GATOR complex protein NPRL2, GATOR complex protein NPRL3, GATOR complex protein DEPDC5, ... (6 entities in total)
• 機能のキーワード: mtorc1 amino-acid sensing lysosome growth control, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 370306.44

構造登録者

Shen, K.,Huang, R.K.,Brignole, E.J.,Yu, Z.,Sabatini, D.M. (登録日: 2018-02-12, 公開日: 2018-03-28, 最終更新日: 2025-05-21)

主引用文献

Shen, K.,Huang, R.K.,Brignole, E.J.,Condon, K.J.,Valenstein, M.L.,Chantranupong, L.,Bomaliyamu, A.,Choe, A.,Hong, C.,Yu, Z.,Sabatini, D.M.
Architecture of the human GATOR1 and GATOR1-Rag GTPases complexes.
Nature, 556:64-69, 2018

PubMed Abstract: Nutrients, such as amino acids and glucose, signal through the Rag GTPases to activate mTORC1. The GATOR1 protein complex-comprising DEPDC5, NPRL2 and NPRL3-regulates the Rag GTPases as a GTPase-activating protein (GAP) for RAGA; loss of GATOR1 desensitizes mTORC1 signalling to nutrient starvation. GATOR1 components have no sequence homology to other proteins, so the function of GATOR1 at the molecular level is currently unknown. Here we used cryo-electron microscopy to solve structures of GATOR1 and GATOR1-Rag GTPases complexes. GATOR1 adopts an extended architecture with a cavity in the middle; NPRL2 links DEPDC5 and NPRL3, and DEPDC5 contacts the Rag GTPase heterodimer. Biochemical analyses reveal that our GATOR1-Rag GTPases structure is inhibitory, and that at least two binding modes must exist between the Rag GTPases and GATOR1. Direct interaction of DEPDC5 with RAGA inhibits GATOR1-mediated stimulation of GTP hydrolysis by RAGA, whereas weaker interactions between the NPRL2-NPRL3 heterodimer and RAGA execute GAP activity. These data reveal the structure of a component of the nutrient-sensing mTORC1 pathway and a non-canonical interaction between a GAP and its substrate GTPase.

PubMed: 29590090
DOI: 10.1038/nature26158

実験手法

ELECTRON MICROSCOPY (4 Å)