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Structural and functional analysis of the role of the chaperonin CCT in mTOR complex assembly
The mechanistic target of rapamycin (mTOR) kinase forms two multi-protein signaling complexes, mTORC1 and mTORC2, which are master regulators of cell growth, metabolism, survival and autophagy. Two of the subunits of these complexes are mLST8 and Raptor, β-propeller proteins that stabilize the mTOR...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599039/ https://www.ncbi.nlm.nih.gov/pubmed/31253771 http://dx.doi.org/10.1038/s41467-019-10781-1 |
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author | Cuéllar, Jorge Ludlam, W. Grant Tensmeyer, Nicole C. Aoba, Takuma Dhavale, Madhura Santiago, César Bueno-Carrasco, M. Teresa Mann, Michael J. Plimpton, Rebecca L. Makaju, Aman Franklin, Sarah Willardson, Barry M. Valpuesta, José M. |
author_facet | Cuéllar, Jorge Ludlam, W. Grant Tensmeyer, Nicole C. Aoba, Takuma Dhavale, Madhura Santiago, César Bueno-Carrasco, M. Teresa Mann, Michael J. Plimpton, Rebecca L. Makaju, Aman Franklin, Sarah Willardson, Barry M. Valpuesta, José M. |
author_sort | Cuéllar, Jorge |
collection | PubMed |
description | The mechanistic target of rapamycin (mTOR) kinase forms two multi-protein signaling complexes, mTORC1 and mTORC2, which are master regulators of cell growth, metabolism, survival and autophagy. Two of the subunits of these complexes are mLST8 and Raptor, β-propeller proteins that stabilize the mTOR kinase and recruit substrates, respectively. Here we report that the eukaryotic chaperonin CCT plays a key role in mTORC assembly and signaling by folding both mLST8 and Raptor. A high resolution (4.0 Å) cryo-EM structure of the human mLST8-CCT intermediate isolated directly from cells shows mLST8 in a near-native state bound to CCT deep within the folding chamber between the two CCT rings, and interacting mainly with the disordered N- and C-termini of specific CCT subunits of both rings. These findings describe a unique function of CCT in mTORC assembly and a distinct binding site in CCT for mLST8, far from those found for similar β-propeller proteins. |
format | Online Article Text |
id | pubmed-6599039 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-65990392019-07-01 Structural and functional analysis of the role of the chaperonin CCT in mTOR complex assembly Cuéllar, Jorge Ludlam, W. Grant Tensmeyer, Nicole C. Aoba, Takuma Dhavale, Madhura Santiago, César Bueno-Carrasco, M. Teresa Mann, Michael J. Plimpton, Rebecca L. Makaju, Aman Franklin, Sarah Willardson, Barry M. Valpuesta, José M. Nat Commun Article The mechanistic target of rapamycin (mTOR) kinase forms two multi-protein signaling complexes, mTORC1 and mTORC2, which are master regulators of cell growth, metabolism, survival and autophagy. Two of the subunits of these complexes are mLST8 and Raptor, β-propeller proteins that stabilize the mTOR kinase and recruit substrates, respectively. Here we report that the eukaryotic chaperonin CCT plays a key role in mTORC assembly and signaling by folding both mLST8 and Raptor. A high resolution (4.0 Å) cryo-EM structure of the human mLST8-CCT intermediate isolated directly from cells shows mLST8 in a near-native state bound to CCT deep within the folding chamber between the two CCT rings, and interacting mainly with the disordered N- and C-termini of specific CCT subunits of both rings. These findings describe a unique function of CCT in mTORC assembly and a distinct binding site in CCT for mLST8, far from those found for similar β-propeller proteins. Nature Publishing Group UK 2019-06-28 /pmc/articles/PMC6599039/ /pubmed/31253771 http://dx.doi.org/10.1038/s41467-019-10781-1 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Cuéllar, Jorge Ludlam, W. Grant Tensmeyer, Nicole C. Aoba, Takuma Dhavale, Madhura Santiago, César Bueno-Carrasco, M. Teresa Mann, Michael J. Plimpton, Rebecca L. Makaju, Aman Franklin, Sarah Willardson, Barry M. Valpuesta, José M. Structural and functional analysis of the role of the chaperonin CCT in mTOR complex assembly |
title | Structural and functional analysis of the role of the chaperonin CCT in mTOR complex assembly |
title_full | Structural and functional analysis of the role of the chaperonin CCT in mTOR complex assembly |
title_fullStr | Structural and functional analysis of the role of the chaperonin CCT in mTOR complex assembly |
title_full_unstemmed | Structural and functional analysis of the role of the chaperonin CCT in mTOR complex assembly |
title_short | Structural and functional analysis of the role of the chaperonin CCT in mTOR complex assembly |
title_sort | structural and functional analysis of the role of the chaperonin cct in mtor complex assembly |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599039/ https://www.ncbi.nlm.nih.gov/pubmed/31253771 http://dx.doi.org/10.1038/s41467-019-10781-1 |
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