Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability

Mol Cell. 2017 Nov 2;68(3):552-565.e8. doi: 10.1016/j.molcel.2017.09.026. Epub 2017 Oct 19.


mTOR complex I (mTORC1) is a central growth regulator that senses amino acids through a pathway that converges on the Rag GTPases, an obligate heterodimer of two related GTPases. Despite their central role in amino acid sensing, it is unknown why the Rag GTPases are heterodimeric and whether their subunits communicate with each other. Here, we find that the binding of guanosine triphosphate (GTP) to one subunit inhibits the binding and induces the hydrolysis of GTP by the other. This intersubunit communication pushes the Rag GTPases into either of two stable configurations, which represent active "on" or "off" states that interconvert via transient intermediates. Subunit coupling confers on the mTORC1 pathway its capacity to respond rapidly to the amino acid level. Thus, the dynamic response of mTORC1 requires intersubunit communication by the Rag GTPases, providing a rationale for why they exist as a dimer and revealing a distinct mode of control for a GTP-binding protein.

Keywords: Rag GTPases; amino acid sensing; enzymatic mechanism; mTORC1; negative cooperativity.

MeSH terms

  • Amino Acids / metabolism*
  • Binding Sites
  • Enzyme Stability
  • Guanosine Triphosphate / metabolism
  • HEK293 Cells
  • Humans
  • Hydrolysis
  • Kinetics
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Models, Molecular
  • Monomeric GTP-Binding Proteins / chemistry
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism*
  • Protein Binding
  • Protein Conformation
  • Protein Multimerization
  • Protein Subunits
  • Signal Transduction
  • Structure-Activity Relationship
  • Transfection


  • Amino Acids
  • Protein Subunits
  • RRAGC protein, human
  • Guanosine Triphosphate
  • Mechanistic Target of Rapamycin Complex 1
  • RRAGA protein, human
  • Monomeric GTP-Binding Proteins