dc.contributor.author | Shen, Kuang | |
dc.contributor.author | Bomaliyamu, Aimaiti | |
dc.contributor.author | Hong, Chuan | |
dc.contributor.author | Yu, Zhiheng | |
dc.contributor.author | Huang, Rick | |
dc.contributor.author | Brignole, Edward J | |
dc.contributor.author | Condon, Kendall Janine | |
dc.contributor.author | Valenstein, Max L. | |
dc.contributor.author | Chantranupong, Lynne | |
dc.contributor.author | Choe, Abigail D. | |
dc.contributor.author | Sabatini, David | |
dc.date.accessioned | 2018-11-05T12:46:12Z | |
dc.date.available | 2018-11-05T12:46:12Z | |
dc.date.issued | 2018-03 | |
dc.identifier.issn | 0028-0836 | |
dc.identifier.issn | 1476-4687 | |
dc.identifier.uri | http://hdl.handle.net/1721.1/118864 | |
dc.description.abstract | Nutrients, such as amino acids and glucose, signal through the Rag GTPases to activate mTORC1. The GATOR1 protein complex - comprising DEPDC5, NPRL2 and NPRL3 - regulates the Rag GTPases as a GTPase-activating protein (GAP) for RAGA; loss of GATOR1 desensitizes mTORC1 signalling to nutrient starvation. GATOR1 components have no sequence homology to other proteins, so the function of GATOR1 at the molecular level is currently unknown. Here we used cryo-electron microscopy to solve structures of GATOR1 and GATOR1-Rag GTPases complexes. GATOR1 adopts an extended architecture with a cavity in the middle; NPRL2 links DEPDC5 and NPRL3, and DEPDC5 contacts the Rag GTPase heterodimer. Biochemical analyses reveal that our GATOR1-Rag GTPases structure is inhibitory, and that at least two binding modes must exist between the Rag GTPases and GATOR1. Direct interaction of DEPDC5 with RAGA inhibits GATOR1-mediated stimulation of GTP hydrolysis by RAGA, whereas weaker interactions between the NPRL2-NPRL3 heterodimer and RAGA execute GAP activity. These data reveal the structure of a component of the nutrient-sensing mTORC1 pathway and a non-canonical interaction between a GAP and its substrate GTPase. | en_US |
dc.description.sponsorship | National Institutes of Health (U.S.) (R01 CA103866) | en_US |
dc.description.sponsorship | National Institutes of Health (U.S.) (R01 CA129105) | en_US |
dc.description.sponsorship | National Institutes of Health (U.S.) (R37 AI047389) | en_US |
dc.description.sponsorship | United States. Department of Defense (W81XWH-15-1-0230) | en_US |
dc.description.sponsorship | National Science Foundation (U.S.) (fellowship 2016197106) | en_US |
dc.publisher | Springer Nature | en_US |
dc.relation.isversionof | http://dx.doi.org/10.1038/NATURE26158 | en_US |
dc.rights | 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. | en_US |
dc.source | PMC | en_US |
dc.title | Architecture of the human GATOR1 and GATOR1–Rag GTPases complexes | en_US |
dc.type | Article | en_US |
dc.identifier.citation | Shen, Kuang, Rick K. Huang, Edward J. Brignole, Kendall J. Condon, Max L. Valenstein, Lynne Chantranupong, Aimaiti Bomaliyamu, et al. “Architecture of the Human GATOR1 and GATOR1–Rag GTPases Complexes.” Nature 556, no. 7699 (March 28, 2018): 64–69. | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Institute for Medical Engineering & Science | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Department of Biology | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Department of Chemistry | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science | en_US |
dc.contributor.mitauthor | Huang, Rick | |
dc.contributor.mitauthor | Brignole, Edward J | |
dc.contributor.mitauthor | Condon, Kendall Janine | |
dc.contributor.mitauthor | Valenstein, Max L. | |
dc.contributor.mitauthor | Chantranupong, Lynne | |
dc.contributor.mitauthor | Choe, Abigail D. | |
dc.contributor.mitauthor | Sabatini, David | |
dc.relation.journal | Nature | en_US |
dc.eprint.version | Author's final manuscript | en_US |
dc.type.uri | http://purl.org/eprint/type/JournalArticle | en_US |
eprint.status | http://purl.org/eprint/status/PeerReviewed | en_US |
dc.date.updated | 2018-10-16T12:58:03Z | |
dspace.orderedauthors | Shen, Kuang; Huang, Rick K.; Brignole, Edward J.; Condon, Kendall J.; Valenstein, Max L.; Chantranupong, Lynne; Bomaliyamu, Aimaiti; Choe, Abigail; Hong, Chuan; Yu, Zhiheng; Sabatini, David M. | en_US |
dspace.embargo.terms | N | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-4285-6128 | |
dc.identifier.orcid | https://orcid.org/0000-0002-9515-8892 | |
dc.identifier.orcid | https://orcid.org/0000-0001-9388-1633 | |
dc.identifier.orcid | https://orcid.org/0000-0002-1446-7256 | |
mit.license | PUBLISHER_POLICY | en_US |