@article{26c77c5c327c416a9cd79faca34c5730,
title = "Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace",
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{\textquoteright}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.",
author = "Maren Heimhalt and Alex Berndt and Jane Wagstaff and Madhanagopal Anandapadamanaban and Olga Perisic and Sarah Maslen and Stephen McLaughlin and Yu, {Conny Wing Heng} and Masson, {Glenn R.} and Andreas Boland and Xiaodan Ni and Keitaro Yamashita and Murshudov, {Garib N.} and Mark Skehel and Freund, {Stefan M.} and Williams, {Roger L.}",
note = "Funding Information: We acknowledge the MRC - Laboratory of Molecular Biology Electron Microscopy Facility for access and support of electron microscopy sample preparation and data collection. We thank Christos Savva, Rangana Warshamanage, Domagoj Bareti{\'c}, Xiao-chen Bai, Rafael Fern{\'a}ndez-Leiro and Sjors Scheres for expert assistance with cryo-EM data collection and processing. We thank Jake Grimmet and Toby Darling for implementing and maintaining the scientific computing infrastructure at the MRC LMB. We thank Christopher Johnson for training for the differential scanning fluorimetry and maintaining the Biophysics facility at the MRC LMB. We thank Yohei Ohashi for help with the initial mTORC1 purification. We thank Jaslyn Wong for providing purified mTORC1 A1459P and RHEB. MA was supported by FEBS fellowship and EMBO Advanced Fellowship (EMBO ALTF 603–2019). The work was supported by the Medical Research Council (MC_U105184308 to RLW) and Cancer Research UK (grant C14801/A21211 to RLW). Publisher Copyright: {\textcopyright} Heimhalt et al.",
year = "2021",
month = sep,
day = "14",
doi = "10.7554/eLife.68799",
language = "English",
volume = "10",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications Ltd.",
}
