Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms
The mechanistic target of rapamycin complex 1 (mTORC1) growth pathway detects nutrients through a variety of sensors and regulators that converge on the Rag GTPases, which form heterodimers consisting of RagA or RagB tightly bound to RagC or RagD and control the subcellular localization of mTORC1. T...
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| Format: | Article |
| Language: | English |
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Proceedings of the National Academy of Sciences
2021
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| Online Access: | https://hdl.handle.net/1721.1/134739 |
| _version_ | 1826208540650373120 |
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| author | Shen, Kuang Sabatini, David M |
| author2 | Whitehead Institute for Biomedical Research |
| author_facet | Whitehead Institute for Biomedical Research Shen, Kuang Sabatini, David M |
| author_sort | Shen, Kuang |
| collection | MIT |
| description | The mechanistic target of rapamycin complex 1 (mTORC1) growth pathway detects nutrients through a variety of sensors and regulators that converge on the Rag GTPases, which form heterodimers consisting of RagA or RagB tightly bound to RagC or RagD and control the subcellular localization of mTORC1. The Rag heterodimer uses a unique "locking" mechanism to stabilize its active (GTPRagA-RagCGDP) or inactive (GDPRagA-RagCGTP) nucleotide states. The Ragulator complex tethers the Rag heterodimer to the lysosomal surface, and the SLC38A9 transmembrane protein is a lysosomal arginine sensor that upon activation stimulates mTORC1 activity through the Rag GTPases. How Ragulator and SLC38A9 control the nucleotide loading state of the Rag GTPases remains incompletely understood. Here we find that Ragulator and SLC38A9 are each unique guanine exchange factors (GEFs) that collectively push the Rag GTPases toward the active state. Ragulator triggers GTP release from RagC, thus resolving the locked inactivated state of the Rag GTPases. Upon arginine binding, SLC38A9 converts RagA from the GDP-to the GTP-loaded state, and therefore activates the Rag GTPase heterodimer. Altogether, Ragulator and SLC38A9 act on the Rag GTPases to activate themTORC1 pathway in response to nutrient sufficiency. |
| first_indexed | 2024-09-23T14:06:55Z |
| format | Article |
| id | mit-1721.1/134739 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T14:06:55Z |
| publishDate | 2021 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1347392023-02-23T20:36:53Z Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms Shen, Kuang Sabatini, David M Whitehead Institute for Biomedical Research Massachusetts Institute of Technology. Department of Biology Howard Hughes Medical Institute Koch Institute for Integrative Cancer Research at MIT The mechanistic target of rapamycin complex 1 (mTORC1) growth pathway detects nutrients through a variety of sensors and regulators that converge on the Rag GTPases, which form heterodimers consisting of RagA or RagB tightly bound to RagC or RagD and control the subcellular localization of mTORC1. The Rag heterodimer uses a unique "locking" mechanism to stabilize its active (GTPRagA-RagCGDP) or inactive (GDPRagA-RagCGTP) nucleotide states. The Ragulator complex tethers the Rag heterodimer to the lysosomal surface, and the SLC38A9 transmembrane protein is a lysosomal arginine sensor that upon activation stimulates mTORC1 activity through the Rag GTPases. How Ragulator and SLC38A9 control the nucleotide loading state of the Rag GTPases remains incompletely understood. Here we find that Ragulator and SLC38A9 are each unique guanine exchange factors (GEFs) that collectively push the Rag GTPases toward the active state. Ragulator triggers GTP release from RagC, thus resolving the locked inactivated state of the Rag GTPases. Upon arginine binding, SLC38A9 converts RagA from the GDP-to the GTP-loaded state, and therefore activates the Rag GTPase heterodimer. Altogether, Ragulator and SLC38A9 act on the Rag GTPases to activate themTORC1 pathway in response to nutrient sufficiency. 2021-10-27T20:08:55Z 2021-10-27T20:08:55Z 2018 2019-09-16T13:39:36Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/134739 en 10.1073/PNAS.1811727115 Proceedings of the National Academy of Sciences of the United States of America 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 Proceedings of the National Academy of Sciences PNAS |
| spellingShingle | Shen, Kuang Sabatini, David M Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms |
| title | Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms |
| title_full | Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms |
| title_fullStr | Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms |
| title_full_unstemmed | Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms |
| title_short | Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms |
| title_sort | ragulator and slc38a9 activate the rag gtpases through noncanonical gef mechanisms |
| url | https://hdl.handle.net/1721.1/134739 |
| work_keys_str_mv | AT shenkuang ragulatorandslc38a9activatetheraggtpasesthroughnoncanonicalgefmechanisms AT sabatinidavidm ragulatorandslc38a9activatetheraggtpasesthroughnoncanonicalgefmechanisms |