Structure of the human mTOR Complex I and its implications for rapamycin inhibition
The mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth in response to the nutrient and energy status of the cell, and its deregulation is common in human cancers. Little is known about the overall architecture and subunit organization of this essential signaling complex. We have...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2012
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| Online Access: | http://hdl.handle.net/1721.1/74548 https://orcid.org/0000-0002-1446-7256 |
| _version_ | 1826203369216147456 |
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| author | Yip, Calvin K. Murata, Kazuyoshi Walz, Thomas Kang, Seong A. Sabatini, David |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Yip, Calvin K. Murata, Kazuyoshi Walz, Thomas Kang, Seong A. Sabatini, David |
| author_sort | Yip, Calvin K. |
| collection | MIT |
| description | The mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth in response to the nutrient and energy status of the cell, and its deregulation is common in human cancers. Little is known about the overall architecture and subunit organization of this essential signaling complex. We have determined the three-dimensional (3D) structure of the fully assembled human mTORC1 by cryo-electron microscopy (cryo-EM). Our analyses reveal that mTORC1 is an obligate dimer with an overall rhomboid shape and a central cavity. The dimeric interfaces are formed by interlocking interactions between the mTOR and raptor subunits. Extended incubation with FKBP12-rapamycin compromises the structural integrity of mTORC1 in a stepwise manner, leading us to propose a model in which rapamycin inhibits mTORC1-mediated phosphorylation of 4E-BP1 and S6K1 through different mechanisms. |
| first_indexed | 2024-09-23T12:35:30Z |
| format | Article |
| id | mit-1721.1/74548 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:35:30Z |
| publishDate | 2012 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/745482022-09-28T08:51:00Z Structure of the human mTOR Complex I and its implications for rapamycin inhibition Yip, Calvin K. Murata, Kazuyoshi Walz, Thomas Kang, Seong A. Sabatini, David Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Sabatini, David M. Kang, Seong A. The mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth in response to the nutrient and energy status of the cell, and its deregulation is common in human cancers. Little is known about the overall architecture and subunit organization of this essential signaling complex. We have determined the three-dimensional (3D) structure of the fully assembled human mTORC1 by cryo-electron microscopy (cryo-EM). Our analyses reveal that mTORC1 is an obligate dimer with an overall rhomboid shape and a central cavity. The dimeric interfaces are formed by interlocking interactions between the mTOR and raptor subunits. Extended incubation with FKBP12-rapamycin compromises the structural integrity of mTORC1 in a stepwise manner, leading us to propose a model in which rapamycin inhibits mTORC1-mediated phosphorylation of 4E-BP1 and S6K1 through different mechanisms. National Institutes of Health (U.S.) (Grant AI47389) National Institutes of Health (U.S.) (Grant CA103866) United States. Dept. of Defense (W81XWH-07-1-0448) W. M. Keck Foundation 2012-11-01T17:21:37Z 2012-11-01T17:21:37Z 2010-06 2010-03 Article http://purl.org/eprint/type/JournalArticle 1097-2765 http://hdl.handle.net/1721.1/74548 Yip, Calvin K. et al. “Structure of the Human mTOR Complex I and Its Implications for Rapamycin Inhibition.” Molecular Cell 38.5 (2010): 768–774. https://orcid.org/0000-0002-1446-7256 en_US http://dx.doi.org/10.1016/j.molcel.2010.05.017 Molecular Cell Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf Elsevier PMC |
| spellingShingle | Yip, Calvin K. Murata, Kazuyoshi Walz, Thomas Kang, Seong A. Sabatini, David Structure of the human mTOR Complex I and its implications for rapamycin inhibition |
| title | Structure of the human mTOR Complex I and its implications for rapamycin inhibition |
| title_full | Structure of the human mTOR Complex I and its implications for rapamycin inhibition |
| title_fullStr | Structure of the human mTOR Complex I and its implications for rapamycin inhibition |
| title_full_unstemmed | Structure of the human mTOR Complex I and its implications for rapamycin inhibition |
| title_short | Structure of the human mTOR Complex I and its implications for rapamycin inhibition |
| title_sort | structure of the human mtor complex i and its implications for rapamycin inhibition |
| url | http://hdl.handle.net/1721.1/74548 https://orcid.org/0000-0002-1446-7256 |
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