Mechanism of arginine sensing by CASTOR1 upstream of mTORC1
The mechanistic Target of Rapamycin Complex 1 (mTORC1) is a major regulator of eukaryotic growth that coordinates anabolic and catabolic cellular processes with inputs such as growth factors and nutrients, including amino acids. In mammals arginine is particularly important, promoting diverse physio...
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Nature Publishing Group
2018
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| Online Access: | http://hdl.handle.net/1721.1/116774 https://orcid.org/0000-0002-9376-3984 https://orcid.org/0000-0001-9388-1633 https://orcid.org/0000-0002-1446-7256 |
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| author | Knockenhauer, Kevin E. Schwartz, Thomas U. Saxton, Robert Andrew Chantranupong, Lynne Sabatini, David |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Knockenhauer, Kevin E. Schwartz, Thomas U. Saxton, Robert Andrew Chantranupong, Lynne Sabatini, David |
| author_sort | Knockenhauer, Kevin E. |
| collection | MIT |
| description | The mechanistic Target of Rapamycin Complex 1 (mTORC1) is a major regulator of eukaryotic growth that coordinates anabolic and catabolic cellular processes with inputs such as growth factors and nutrients, including amino acids. In mammals arginine is particularly important, promoting diverse physiological effects such as immune cell activation, insulin secretion, and muscle growth, largely mediated through activation of mTORC1 (refs 4, 5, 6, 7).Arginine activates mTORC1 upstream of the Rag family of GTPases, through either the lysosomal amino acid transporter SLC38A9 or the GATOR2-interacting Cellular Arginine Sensor for mTORC1 (CASTOR1). However, the mechanism by which the mTORC1 pathway detects and transmits this arginine signal has been elusive. Here, we present the 1.8 Å crystal structure of arginine-bound CASTOR1. Homodimeric CASTOR1 binds arginine at the interface of two Aspartate kinase, Chorismate mutase, TyrA (ACT) domains, enabling allosteric control of the adjacent GATOR2-binding site to trigger dissociation from GATOR2 and downstream activation of mTORC1. Our data reveal that CASTOR1 shares substantial structural homology with the lysine-binding regulatory domain of prokaryotic aspartate kinases, suggesting that the mTORC1 pathway exploited an ancient, amino-acid-dependent allosteric mechanism to acquire arginine sensitivity. Together, these results establish a structural basis for arginine sensing by the mTORC1 pathway and provide insights into the evolution of a mammalian nutrient sensor. |
| first_indexed | 2024-09-23T11:27:46Z |
| format | Article |
| id | mit-1721.1/116774 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T11:27:46Z |
| publishDate | 2018 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1167742022-10-01T03:47:50Z Mechanism of arginine sensing by CASTOR1 upstream of mTORC1 Knockenhauer, Kevin E. Schwartz, Thomas U. Saxton, Robert Andrew Chantranupong, Lynne Sabatini, David Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Saxton, Robert Andrew Chantranupong, Lynne Sabatini, David The mechanistic Target of Rapamycin Complex 1 (mTORC1) is a major regulator of eukaryotic growth that coordinates anabolic and catabolic cellular processes with inputs such as growth factors and nutrients, including amino acids. In mammals arginine is particularly important, promoting diverse physiological effects such as immune cell activation, insulin secretion, and muscle growth, largely mediated through activation of mTORC1 (refs 4, 5, 6, 7).Arginine activates mTORC1 upstream of the Rag family of GTPases, through either the lysosomal amino acid transporter SLC38A9 or the GATOR2-interacting Cellular Arginine Sensor for mTORC1 (CASTOR1). However, the mechanism by which the mTORC1 pathway detects and transmits this arginine signal has been elusive. Here, we present the 1.8 Å crystal structure of arginine-bound CASTOR1. Homodimeric CASTOR1 binds arginine at the interface of two Aspartate kinase, Chorismate mutase, TyrA (ACT) domains, enabling allosteric control of the adjacent GATOR2-binding site to trigger dissociation from GATOR2 and downstream activation of mTORC1. Our data reveal that CASTOR1 shares substantial structural homology with the lysine-binding regulatory domain of prokaryotic aspartate kinases, suggesting that the mTORC1 pathway exploited an ancient, amino-acid-dependent allosteric mechanism to acquire arginine sensitivity. Together, these results establish a structural basis for arginine sensing by the mTORC1 pathway and provide insights into the evolution of a mammalian nutrient sensor. National Institutes of Health (U.S.) (Grant R01CA103866) National Institutes of Health (U.S.) (Grant AI47389) United States. Department of Defense (Award W81XWH-07-0448) National Institutes of Health (U.S.) (Grant F31 CA180271) 2018-07-03T19:22:01Z 2018-07-03T19:22:01Z 2016-08 2016-02 2018-07-03T18:18:05Z Article http://purl.org/eprint/type/JournalArticle 0028-0836 1476-4687 http://hdl.handle.net/1721.1/116774 Saxton, Robert A. et al. “Mechanism of Arginine Sensing by CASTOR1 Upstream of mTORC1.” Nature 536, 7615 (August 2016): 229–233 © 2016 Macmillan Publishers Limited, part of Springer Nature https://orcid.org/0000-0002-9376-3984 https://orcid.org/0000-0001-9388-1633 https://orcid.org/0000-0002-1446-7256 http://dx.doi.org/10.1038/NATURE19079 Nature Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Nature Publishing Group PMC |
| spellingShingle | Knockenhauer, Kevin E. Schwartz, Thomas U. Saxton, Robert Andrew Chantranupong, Lynne Sabatini, David Mechanism of arginine sensing by CASTOR1 upstream of mTORC1 |
| title | Mechanism of arginine sensing by CASTOR1 upstream of mTORC1 |
| title_full | Mechanism of arginine sensing by CASTOR1 upstream of mTORC1 |
| title_fullStr | Mechanism of arginine sensing by CASTOR1 upstream of mTORC1 |
| title_full_unstemmed | Mechanism of arginine sensing by CASTOR1 upstream of mTORC1 |
| title_short | Mechanism of arginine sensing by CASTOR1 upstream of mTORC1 |
| title_sort | mechanism of arginine sensing by castor1 upstream of mtorc1 |
| url | http://hdl.handle.net/1721.1/116774 https://orcid.org/0000-0002-9376-3984 https://orcid.org/0000-0001-9388-1633 https://orcid.org/0000-0002-1446-7256 |
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