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

eLife

Andreas Boland¹  Mark Skehel²  Keitaro Yamashita²  Jane Wagstaff²  Sarah Maslen²  Stefan M Freund²  Garib N Murshudov²  Conny Wing-Heng Yu²  Alex Berndt²  Xiaodan Ni²  Stephen McLaughlin²  Madhanagopal Anandapadamanaban²  Maren Heimhalt²  Olga Perisic²  Glenn R Masson²  Roger L Williams² 

[1] Department of Molecular Biology, University of Geneva, Geneva, Switzerland;MRC Laboratory of Molecular Biology, Cambridge, United Kingdom;

关键词: mTOR;    DEPTOR;    cryo-EM;    partial inhibition;    cancer;    signal transduction;    Human;   

DOI  :  10.7554/eLife.68799

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY