Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability
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Author(s)
Shen, Kuang
Choe, Abigail D.
Sabatini, David
Date Issued
October 2017
Journal
Molecular Cell
Publisher
Elsevier BV
Citation
Shen, Kuang et al. “Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability.” Molecular Cell 68, 3 (November 2017): 552–565 © 2017 Elsevier Inc
Version
Author's final manuscript
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. The Rag GTPase heterodimer transmits amino acid signals to mTORC1. It is distinct from canonical small signaling GTPases because of its obligate heterodimeric nature. Shen et al. used the kinetic method to analyze communication between Rag GTPase subunits, revealing a unique intersubunit locking mechanism that controls its nucleotide state. Keywords:
Rag GTPases; mTORC1; amino acid sensing; negative cooperativity; enzymatic mechanism
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.MOLCEL.2017.09.026
