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

Kuang Shen; Abigail Choe; David M Sabatini

doi:10.1016/j.molcel.2017.09.026

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.

Authors

Kuang Shen¹, Abigail Choe², David M Sabatini³

Affiliations

¹ Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA.
² Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA.
³ Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. Electronic address: sabatini@wi.mit.edu.

Abstract

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

Substances

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

Abstract

MeSH terms

Substances

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