Regulation of human mTOR complexes by DEPTOR
The vertebrate-specific DEP domain-containing mTOR interacting protein (DEPTOR), an oncoprotein or tumor suppressor, has important roles in metabolism, immunity, and cancer. It is the only protein that binds and regulates both complexes of mammalian target of rapamycin (mTOR), a central regulator of...
| 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 |
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| Online Access: | https://elifesciences.org/articles/70871 |
| _version_ | 1818026704774365184 |
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| author | Matthias Wälchli Karolin Berneiser Francesca Mangia Stefan Imseng Louise-Marie Craigie Edward Stuttfeld Michael N Hall Timm Maier |
| author_facet | Matthias Wälchli Karolin Berneiser Francesca Mangia Stefan Imseng Louise-Marie Craigie Edward Stuttfeld Michael N Hall Timm Maier |
| author_sort | Matthias Wälchli |
| collection | DOAJ |
| description | The vertebrate-specific DEP domain-containing mTOR interacting protein (DEPTOR), an oncoprotein or tumor suppressor, has important roles in metabolism, immunity, and cancer. It is the only protein that binds and regulates both complexes of mammalian target of rapamycin (mTOR), a central regulator of cell growth. Biochemical analysis and cryo-EM reconstructions of DEPTOR bound to human mTOR complex 1 (mTORC1) and mTORC2 reveal that both structured regions of DEPTOR, the PDZ domain and the DEP domain tandem (DEPt), are involved in mTOR interaction. The PDZ domain binds tightly with mildly activating effect, but then acts as an anchor for DEPt association that allosterically suppresses mTOR activation. The binding interfaces of the PDZ domain and DEPt also support further regulation by other signaling pathways. A separate, substrate-like mode of interaction for DEPTOR phosphorylation by mTOR complexes rationalizes inhibition of non-stimulated mTOR activity at higher DEPTOR concentrations. The multifaceted interplay between DEPTOR and mTOR provides a basis for understanding the divergent roles of DEPTOR in physiology and opens new routes for targeting the mTOR-DEPTOR interaction in disease. |
| first_indexed | 2024-12-10T04:36:14Z |
| format | Article |
| id | doaj.art-537101079ab14803a9dd0b1df95fd193 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T04:36:14Z |
| publishDate | 2021-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-537101079ab14803a9dd0b1df95fd1932022-12-22T02:02:00ZengeLife Sciences Publications LtdeLife2050-084X2021-09-011010.7554/eLife.70871Regulation of human mTOR complexes by DEPTORMatthias Wälchli0https://orcid.org/0000-0001-9354-3079Karolin Berneiser1https://orcid.org/0000-0002-0963-8559Francesca Mangia2https://orcid.org/0000-0001-5430-397XStefan Imseng3https://orcid.org/0000-0002-0248-0795Louise-Marie Craigie4Edward Stuttfeld5https://orcid.org/0000-0003-3932-9076Michael N Hall6https://orcid.org/0000-0002-2998-0757Timm Maier7https://orcid.org/0000-0002-7459-1363Biozentrum, University of Basel, Basel, SwitzerlandBiozentrum, University of Basel, Basel, SwitzerlandBiozentrum, University of Basel, Basel, SwitzerlandBiozentrum, University of Basel, Basel, SwitzerlandBiozentrum, University of Basel, Basel, SwitzerlandBiozentrum, University of Basel, Basel, SwitzerlandBiozentrum, University of Basel, Basel, SwitzerlandBiozentrum, University of Basel, Basel, SwitzerlandThe vertebrate-specific DEP domain-containing mTOR interacting protein (DEPTOR), an oncoprotein or tumor suppressor, has important roles in metabolism, immunity, and cancer. It is the only protein that binds and regulates both complexes of mammalian target of rapamycin (mTOR), a central regulator of cell growth. Biochemical analysis and cryo-EM reconstructions of DEPTOR bound to human mTOR complex 1 (mTORC1) and mTORC2 reveal that both structured regions of DEPTOR, the PDZ domain and the DEP domain tandem (DEPt), are involved in mTOR interaction. The PDZ domain binds tightly with mildly activating effect, but then acts as an anchor for DEPt association that allosterically suppresses mTOR activation. The binding interfaces of the PDZ domain and DEPt also support further regulation by other signaling pathways. A separate, substrate-like mode of interaction for DEPTOR phosphorylation by mTOR complexes rationalizes inhibition of non-stimulated mTOR activity at higher DEPTOR concentrations. The multifaceted interplay between DEPTOR and mTOR provides a basis for understanding the divergent roles of DEPTOR in physiology and opens new routes for targeting the mTOR-DEPTOR interaction in disease.https://elifesciences.org/articles/70871DEPTORmTORsignalingmetabolismcancercryo-EM |
| spellingShingle | Matthias Wälchli Karolin Berneiser Francesca Mangia Stefan Imseng Louise-Marie Craigie Edward Stuttfeld Michael N Hall Timm Maier Regulation of human mTOR complexes by DEPTOR eLife DEPTOR mTOR signaling metabolism cancer cryo-EM |
| title | Regulation of human mTOR complexes by DEPTOR |
| title_full | Regulation of human mTOR complexes by DEPTOR |
| title_fullStr | Regulation of human mTOR complexes by DEPTOR |
| title_full_unstemmed | Regulation of human mTOR complexes by DEPTOR |
| title_short | Regulation of human mTOR complexes by DEPTOR |
| title_sort | regulation of human mtor complexes by deptor |
| topic | DEPTOR mTOR signaling metabolism cancer cryo-EM |
| url | https://elifesciences.org/articles/70871 |
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