Structural basis for Ragulator functioning as a scaffold in membrane-anchoring of Rag GTPases and mTORC1

Nat Commun. 2017 Nov 9;8(1):1394. doi: 10.1038/s41467-017-01567-4.

Abstract

Amino acid-dependent activation of the mechanistic target of rapamycin complex 1 (mTORC1) is mediated by Rag GTPases, which are recruited to the lysosome by the Ragulator complex consisting of p18, MP1, p14, HBXIP and C7orf59; however, the molecular mechanism is elusive. Here, we report the crystal structure of Ragulator, in which p18 wraps around the MP1-p14 and C7orf59-HBXIP heterodimers and the interactions of p18 with MP1, C7orf59, and HBXIP are essential for the assembly of Ragulator. There are two binding sites for the Roadblock domains of Rag GTPases: helix α1 of p18 and the two helices side of MP1-p14. The interaction of Ragulator with Rag GTPases is required for their cellular co-localization and can be competitively inhibited by C17orf59. Collectively, our data indicate that Ragulator functions as a scaffold to recruit Rag GTPases to lysosomal membrane in mTORC1 signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Binding Sites
  • Cell Line
  • Cyclin-Dependent Kinase Inhibitor p18 / metabolism
  • Guanine Nucleotide Exchange Factors / metabolism
  • HEK293 Cells
  • Humans
  • Intracellular Membranes / metabolism*
  • Lysosomes / metabolism*
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Membrane Proteins / metabolism*
  • Monomeric GTP-Binding Proteins / metabolism*
  • Protein Binding
  • Protein Structure, Secondary / physiology
  • Signal Transduction

Substances

  • Adaptor Proteins, Signal Transducing
  • CDKN2C protein, human
  • Cyclin-Dependent Kinase Inhibitor p18
  • Guanine Nucleotide Exchange Factors
  • LAMTOR4 protein, human
  • LAMTOR5 protein, human
  • Membrane Proteins
  • ragulator complex protein LAMTOR2, human
  • Mechanistic Target of Rapamycin Complex 1
  • RRAGA protein, human
  • Monomeric GTP-Binding Proteins