Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway
Eukaryotic cells coordinate growth with the availability of nutrients through the mechanistic target of rapamycin complex 1 (mTORC1), a master growth regulator. Leucine is of particular importance and activates mTORC1 via the Rag guanosine triphosphatases and their regulators GATOR1 and GATOR2. Sest...
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| Format: | Article |
| Language: | en_US |
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American Association for the Advancement of Science (AAAS)
2017
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| Online Access: | http://hdl.handle.net/1721.1/108103 https://orcid.org/0000-0002-9376-3984 https://orcid.org/0000-0002-9535-7664 https://orcid.org/0000-0001-9388-1633 https://orcid.org/0000-0002-4227-5163 https://orcid.org/0000-0001-8012-1512 https://orcid.org/0000-0002-1446-7256 https://orcid.org/0000-0003-2265-5174 https://orcid.org/0000-0003-3688-2378 |
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| author | Saxton, Robert Andrew Wolfson, Rachel Laura Chantranupong, Lynne Wang, Tim Schwartz, Thomas Sabatini, David Knockenhauer, Kevin Edward Pacold, Michael Edward |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Saxton, Robert Andrew Wolfson, Rachel Laura Chantranupong, Lynne Wang, Tim Schwartz, Thomas Sabatini, David Knockenhauer, Kevin Edward Pacold, Michael Edward |
| author_sort | Saxton, Robert Andrew |
| collection | MIT |
| description | Eukaryotic cells coordinate growth with the availability of nutrients through the mechanistic target of rapamycin complex 1 (mTORC1), a master growth regulator. Leucine is of particular importance and activates mTORC1 via the Rag guanosine triphosphatases and their regulators GATOR1 and GATOR2. Sestrin2 interacts with GATOR2 and is a leucine sensor. Here we present the 2.7 angstrom crystal structure of Sestrin2 in complex with leucine. Leucine binds through a single pocket that coordinates its charged functional groups and confers specificity for the hydrophobic side chain. A loop encloses leucine and forms a lid-latch mechanism required for binding. A structure-guided mutation in Sestrin2 that decreases its affinity for leucine leads to a concomitant increase in the leucine concentration required for mTORC1 activation in cells. These results provide a structural mechanism of amino acid sensing by the mTORC1 pathway. |
| first_indexed | 2024-09-23T14:15:25Z |
| format | Article |
| id | mit-1721.1/108103 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:15:25Z |
| publishDate | 2017 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/1081032022-10-01T20:10:07Z Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway Saxton, Robert Andrew Wolfson, Rachel Laura Chantranupong, Lynne Wang, Tim Schwartz, Thomas Sabatini, David Knockenhauer, Kevin Edward Pacold, Michael Edward Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Saxton, Robert Andrew Wolfson, Rachel Laura Chantranupong, Lynne Wang, Tim Schwartz, Thomas Sabatini, David Knockenhauer, Kevin Edward Pacold, Michael E Eukaryotic cells coordinate growth with the availability of nutrients through the mechanistic target of rapamycin complex 1 (mTORC1), a master growth regulator. Leucine is of particular importance and activates mTORC1 via the Rag guanosine triphosphatases and their regulators GATOR1 and GATOR2. Sestrin2 interacts with GATOR2 and is a leucine sensor. Here we present the 2.7 angstrom crystal structure of Sestrin2 in complex with leucine. Leucine binds through a single pocket that coordinates its charged functional groups and confers specificity for the hydrophobic side chain. A loop encloses leucine and forms a lid-latch mechanism required for binding. A structure-guided mutation in Sestrin2 that decreases its affinity for leucine leads to a concomitant increase in the leucine concentration required for mTORC1 activation in cells. These results provide a structural mechanism of amino acid sensing by the mTORC1 pathway. United States. Department of Defense (W81XWH-07- 0448) Damon Runyon Cancer Research Foundation (DRG-112-12) National Institutes of Health (U.S.) (Predoctoral Training Grant T32GM007287) National Institutes of Health (U.S.) (Grants R01CA103866, AI47389, T32 GM007753, F30 CA189333, F31 CA180271, and F31 CA189437) United States. Dept. of Defense. Breast Cancer Research Program (Postdoctoral Fellowship BC120208) Massachusetts Institute of Technology. Office of the Dean for Graduate Education (Whitaker Health Sciences Fund Fellowship) Damon Runyon Cancer Research Foundation (Sally Gordon Fellowship DRG-112-12) 2017-04-13T14:36:24Z 2017-04-13T14:36:24Z 2016-11 2015-08 Article http://purl.org/eprint/type/JournalArticle 0036-8075 1095-9203 http://hdl.handle.net/1721.1/108103 Saxton, R. A., K. E. Knockenhauer, R. L. Wolfson, L. Chantranupong, M. E. Pacold, T. Wang, T. U. Schwartz, and D. M. Sabatini. “Structural Basis for Leucine Sensing by the Sestrin2-mTORC1 Pathway.” Science 351, no. 6268 (November 19, 2015): 53–58. © 2016 American Association for the Advancement of Science https://orcid.org/0000-0002-9376-3984 https://orcid.org/0000-0002-9535-7664 https://orcid.org/0000-0001-9388-1633 https://orcid.org/0000-0002-4227-5163 https://orcid.org/0000-0001-8012-1512 https://orcid.org/0000-0002-1446-7256 https://orcid.org/0000-0003-2265-5174 https://orcid.org/0000-0003-3688-2378 en_US http://dx.doi.org/10.1126/science.aad2087 Science 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 American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | Saxton, Robert Andrew Wolfson, Rachel Laura Chantranupong, Lynne Wang, Tim Schwartz, Thomas Sabatini, David Knockenhauer, Kevin Edward Pacold, Michael Edward Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway |
| title | Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway |
| title_full | Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway |
| title_fullStr | Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway |
| title_full_unstemmed | Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway |
| title_short | Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway |
| title_sort | structural basis for leucine sensing by the sestrin2 mtorc1 pathway |
| url | http://hdl.handle.net/1721.1/108103 https://orcid.org/0000-0002-9376-3984 https://orcid.org/0000-0002-9535-7664 https://orcid.org/0000-0001-9388-1633 https://orcid.org/0000-0002-4227-5163 https://orcid.org/0000-0001-8012-1512 https://orcid.org/0000-0002-1446-7256 https://orcid.org/0000-0003-2265-5174 https://orcid.org/0000-0003-3688-2378 |
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