Journal Article

Structural basis for the assembly of the Ragulator-Rag GTPase complex

Yonehara, Ryo, Nada, Shigeyuki, Kitamura, Ayaka, Nakatsumi, Hirokazu, Nakayama, Keiichi I., Standley, Daron M., Okada, Masato, Nakai, Tomokazu, Nakagawa, Atsushi, Yamashita, Eiki, Nakai, Masahiro, Ogawa, Akira, Li, Songling

2017

Overview

The mechanistic target of rapamycin complex 1 (mTORC1) plays a central role in regulating cell growth and metabolism by responding to cellular nutrient conditions. The activity of mTORC1 is controlled by Rag GTPases, which are anchored to lysosomes via Ragulator, a pentameric protein complex consisting of membrane-anchored p18/LAMTOR1 and two roadblock heterodimers. Here we report the crystal structure of Ragulator in complex with the roadblock domains of RagA-C, which helps to elucidate the molecular basis for the regulation of Rag GTPases. In the structure, p18 wraps around the three pairs of roadblock heterodimers to tandemly assemble them onto lysosomes. Cellular and in vitro analyses further demonstrate that p18 is required for Ragulator-Rag GTPase assembly and amino acid-dependent activation of mTORC1. These results establish p18 as a critical organizing scaffold for the Ragulator-Rag GTPase complex, which may provide a platform for nutrient sensing on lysosomes. mTORC1 activity is controlled through Rag GTPases, which are anchored to the lysosome through the Ragulator. Here, the authors give molecular insights into Ragulator-Rag GTPase assembly and present the crystal structures of the Ragulator alone and in complex with the RagA-C roadblock domains.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/45/535/1266 / 631/80/86/2369 / Adaptor Proteins, Signal Transducing - chemistry / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Amino acids / Assembly / Cell growth / Crystal structure / Data collection / Growth factors / Guanosine triphosphatases / Humanities and Social Sciences / Humans / Hydrogen bonds / Kinases / Ligands / Lysosomes / Lysosomes - chemistry / Lysosomes - enzymology / Lysosomes - genetics / Lysosomes - metabolism / Mechanistic Target of Rapamycin Complex 1 - chemistry / Mechanistic Target of Rapamycin Complex 1 - genetics / Mechanistic Target of Rapamycin Complex 1 - metabolism / Membrane proteins / Metabolism / Monomeric GTP-Binding Proteins - chemistry / Monomeric GTP-Binding Proteins - genetics / Monomeric GTP-Binding Proteins - metabolism / multidisciplinary / Multiprotein Complexes - chemistry / Multiprotein Complexes - genetics / Multiprotein Complexes - metabolism / Nutrients / Protein Binding / Protein Multimerization / Proteins / Rapamycin / Science / Science (multidisciplinary) / TOR protein