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Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace.

Published version
Peer-reviewed

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Authors

Berndt, Alex 
Wagstaff, Jane 
Anandapadamanaban, Madhanagopal  ORCID logo  https://orcid.org/0000-0002-4237-0048
Perisic, Olga 

Abstract

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.

Description

Keywords

DEPTOR, biochemistry, cancer, chemical biology, cryo-EM, human, mTOR, molecular biophysics, partial inhibition, signal transduction, structural biology, Binding Sites, Cryoelectron Microscopy, Escherichia coli, Gene Expression Regulation, Humans, Image Processing, Computer-Assisted, Intracellular Signaling Peptides and Proteins, Mechanistic Target of Rapamycin Complex 1, Models, Molecular, PDZ Domains, Protein Binding, Protein Conformation, Recombinant Proteins, TOR Serine-Threonine Kinases

Journal Title

Elife

Conference Name

Journal ISSN

2050-084X
2050-084X

Volume Title

10

Publisher

eLife Sciences Publications, Ltd
Sponsorship
Medical Research Council (MC_U105184308)
Cancer Research UK (C14801/A21211)
EMBO (EMBO ALTF 603–2019)
FEBS (Fellowship)