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

Nat Commun. 2017 Nov 20;8(1):1625. doi: 10.1038/s41467-017-01762-3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Humans
  • 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
  • Monomeric GTP-Binding Proteins / chemistry*
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism
  • Multiprotein Complexes / chemistry*
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Protein Binding
  • Protein Multimerization

Substances

  • Adaptor Proteins, Signal Transducing
  • Multiprotein Complexes
  • RRAGC protein, human
  • ragulator complex protein LAMTOR2, human
  • Mechanistic Target of Rapamycin Complex 1
  • RRAGA protein, human
  • Monomeric GTP-Binding Proteins