Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability
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 s...
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| Format: | Article |
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Elsevier BV
2018
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| Online Access: | http://hdl.handle.net/1721.1/119190 https://orcid.org/0000-0002-1446-7256 |
| _version_ | 1826203955347062784 |
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| author | Shen, Kuang Choe, Abigail D. Sabatini, David |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Shen, Kuang Choe, Abigail D. Sabatini, David |
| author_sort | Shen, Kuang |
| collection | MIT |
| description | 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 |
| first_indexed | 2024-09-23T12:46:04Z |
| format | Article |
| id | mit-1721.1/119190 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T12:46:04Z |
| publishDate | 2018 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1191902022-10-01T11:02:20Z Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability Shen, Kuang Choe, Abigail D. Sabatini, David 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 Shen, Kuang Choe, Abigail D. Sabatini, David 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 National Institutes of Health (U.S.) (Grant R01CA103866) National Institutes of Health (U.S.) (Grant R01CA129105) National Institutes of Health (U.S.) (Grant R37AI47389) United States. Department of Energy (Grant W81XWH-15-1-0230) 2018-11-19T16:36:20Z 2018-11-19T16:36:20Z 2017-10 2017-08 2018-11-06T14:47:16Z Article http://purl.org/eprint/type/JournalArticle 1097-2765 1097-4164 http://hdl.handle.net/1721.1/119190 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 https://orcid.org/0000-0002-1446-7256 http://dx.doi.org/10.1016/J.MOLCEL.2017.09.026 Molecular Cell Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV PMC |
| spellingShingle | Shen, Kuang Choe, Abigail D. Sabatini, David Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability |
| title | Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability |
| title_full | Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability |
| title_fullStr | Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability |
| title_full_unstemmed | Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability |
| title_short | Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability |
| title_sort | intersubunit crosstalk in the rag gtpase heterodimer enables mtorc1 to respond rapidly to amino acid availability |
| url | http://hdl.handle.net/1721.1/119190 https://orcid.org/0000-0002-1446-7256 |
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