7PE9

cryo-EM structure of DEPTOR bound to human mTOR complex 2, DEPt-bound subset local refinement

Summary for 7PE9

• Entry DOI: 10.2210/pdb7pe9/pdb
• EMDB information: 13349
• Descriptor: Serine/threonine-protein kinase mTOR, Target of rapamycin complex subunit LST8, Rapamycin-insensitive companion of mTOR, ... (8 entities in total)
• Functional Keywords: deptor, mtor, regulator, inhibitor, mtorc2, dep-domain, pdz-domain, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 626047.02

Authors

Waelchli, M.,Maier, T. (deposition date: 2021-08-09, release date: 2021-09-08, Last modification date: 2021-09-29)

Primary citation

Walchli, M.,Berneiser, K.,Mangia, F.,Imseng, S.,Craigie, L.M.,Stuttfeld, E.,Hall, M.N.,Maier, T.
Regulation of human mTOR complexes by DEPTOR.
Elife, 10:-, 2021

PubMed Abstract: 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.

PubMed: 34519268
DOI: 10.7554/eLife.70871

Experimental method

ELECTRON MICROSCOPY (3.7 Å)