Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace
The mTORC1 kinase complex regulates cell growth, proliferation, and survival. Because mis-regulation of DEPTOR, an endogenous mTORC1 inhibitor, is associated with some cancers, we reconstituted mTORC1 with DEPTOR to understand its function. We find that DEPTOR is a unique partial mTORC1 inhibitor th...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-09-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/68799 |
| _version_ | 1811236094395547648 |
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| author | Maren Heimhalt Alex Berndt Jane Wagstaff Madhanagopal Anandapadamanaban Olga Perisic Sarah Maslen Stephen McLaughlin Conny Wing-Heng Yu Glenn R Masson Andreas Boland Xiaodan Ni Keitaro Yamashita Garib N Murshudov Mark Skehel Stefan M Freund Roger L Williams |
| author_facet | Maren Heimhalt Alex Berndt Jane Wagstaff Madhanagopal Anandapadamanaban Olga Perisic Sarah Maslen Stephen McLaughlin Conny Wing-Heng Yu Glenn R Masson Andreas Boland Xiaodan Ni Keitaro Yamashita Garib N Murshudov Mark Skehel Stefan M Freund Roger L Williams |
| author_sort | Maren Heimhalt |
| collection | DOAJ |
| description | The mTORC1 kinase complex regulates cell growth, proliferation, and survival. Because mis-regulation of DEPTOR, an endogenous mTORC1 inhibitor, is associated with some cancers, we reconstituted mTORC1 with DEPTOR to understand its function. We find that DEPTOR is a unique partial mTORC1 inhibitor that may have evolved to preserve feedback inhibition of PI3K. Counterintuitively, mTORC1 activated by RHEB or oncogenic mutation is much more potently inhibited by DEPTOR. Although DEPTOR partially inhibits mTORC1, mTORC1 prevents this inhibition by phosphorylating DEPTOR, a mutual antagonism that requires no exogenous factors. Structural analyses of the mTORC1/DEPTOR complex showed DEPTOR’s PDZ domain interacting with the mTOR FAT region, and the unstructured linker preceding the PDZ binding to the mTOR FRB domain. The linker and PDZ form the minimal inhibitory unit, but the N-terminal tandem DEP domains also significantly contribute to inhibition. |
| first_indexed | 2024-04-12T12:03:01Z |
| format | Article |
| id | doaj.art-f3e3156092d447fd9fa28ea08dad4816 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:03:01Z |
| publishDate | 2021-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-f3e3156092d447fd9fa28ea08dad48162022-12-22T03:33:48ZengeLife Sciences Publications LtdeLife2050-084X2021-09-011010.7554/eLife.68799Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embraceMaren Heimhalt0https://orcid.org/0000-0001-9993-2884Alex Berndt1Jane Wagstaff2Madhanagopal Anandapadamanaban3https://orcid.org/0000-0002-4237-0048Olga Perisic4Sarah Maslen5Stephen McLaughlin6https://orcid.org/0000-0001-9135-6253Conny Wing-Heng Yu7Glenn R Masson8Andreas Boland9Xiaodan Ni10Keitaro Yamashita11Garib N Murshudov12Mark Skehel13Stefan M Freund14Roger L Williams15https://orcid.org/0000-0001-7754-4207MRC Laboratory of Molecular Biology, Cambridge, United KingdomMRC Laboratory of Molecular Biology, Cambridge, United KingdomMRC Laboratory of Molecular Biology, Cambridge, United KingdomMRC Laboratory of Molecular Biology, Cambridge, United KingdomMRC Laboratory of Molecular Biology, Cambridge, United KingdomMRC Laboratory of Molecular Biology, Cambridge, United KingdomMRC Laboratory of Molecular Biology, Cambridge, United KingdomMRC Laboratory of Molecular Biology, Cambridge, United KingdomMRC Laboratory of Molecular Biology, Cambridge, United KingdomDepartment of Molecular Biology, University of Geneva, Geneva, SwitzerlandMRC Laboratory of Molecular Biology, Cambridge, United KingdomMRC Laboratory of Molecular Biology, Cambridge, United KingdomMRC Laboratory of Molecular Biology, Cambridge, United KingdomMRC Laboratory of Molecular Biology, Cambridge, United KingdomMRC Laboratory of Molecular Biology, Cambridge, United KingdomMRC Laboratory of Molecular Biology, Cambridge, United KingdomThe mTORC1 kinase complex regulates cell growth, proliferation, and survival. Because mis-regulation of DEPTOR, an endogenous mTORC1 inhibitor, is associated with some cancers, we reconstituted mTORC1 with DEPTOR to understand its function. We find that DEPTOR is a unique partial mTORC1 inhibitor that may have evolved to preserve feedback inhibition of PI3K. Counterintuitively, mTORC1 activated by RHEB or oncogenic mutation is much more potently inhibited by DEPTOR. Although DEPTOR partially inhibits mTORC1, mTORC1 prevents this inhibition by phosphorylating DEPTOR, a mutual antagonism that requires no exogenous factors. Structural analyses of the mTORC1/DEPTOR complex showed DEPTOR’s PDZ domain interacting with the mTOR FAT region, and the unstructured linker preceding the PDZ binding to the mTOR FRB domain. The linker and PDZ form the minimal inhibitory unit, but the N-terminal tandem DEP domains also significantly contribute to inhibition.https://elifesciences.org/articles/68799mTORDEPTORcryo-EMpartial inhibitioncancersignal transduction |
| spellingShingle | Maren Heimhalt Alex Berndt Jane Wagstaff Madhanagopal Anandapadamanaban Olga Perisic Sarah Maslen Stephen McLaughlin Conny Wing-Heng Yu Glenn R Masson Andreas Boland Xiaodan Ni Keitaro Yamashita Garib N Murshudov Mark Skehel Stefan M Freund Roger L Williams Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace eLife mTOR DEPTOR cryo-EM partial inhibition cancer signal transduction |
| title | Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace |
| title_full | Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace |
| title_fullStr | Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace |
| title_full_unstemmed | Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace |
| title_short | Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace |
| title_sort | bipartite binding and partial inhibition links deptor and mtor in a mutually antagonistic embrace |
| topic | mTOR DEPTOR cryo-EM partial inhibition cancer signal transduction |
| url | https://elifesciences.org/articles/68799 |
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