PMID- 33158864
OWN - NLM
STAT- MEDLINE
DCOM- 20220414
LR  - 20220414
IS  - 2375-2548 (Electronic)
IS  - 2375-2548 (Linking)
VI  - 6
IP  - 45
DP  - 2020 Nov
TI  - The 3.2-A resolution structure of human mTORC2.
LID - 10.1126/sciadv.abc1251 [doi]
LID - eabc1251
AB  - The protein kinase mammalian target of rapamycin (mTOR) is the central regulator 
      of cell growth. Aberrant mTOR signaling is linked to cancer, diabetes, and 
      neurological disorders. mTOR exerts its functions in two distinct multiprotein 
      complexes, mTORC1 and mTORC2. Here, we report a 3.2-A resolution cryo-EM 
      reconstruction of mTORC2. It reveals entangled folds of the defining Rictor and 
      the substrate-binding SIN1 subunits, identifies the carboxyl-terminal domain of 
      Rictor as the source of the rapamycin insensitivity of mTORC2, and resolves 
      mechanisms for mTORC2 regulation by complex destabilization. Two previously 
      uncharacterized small-molecule binding sites are visualized, an inositol 
      hexakisphosphate (InsP6) pocket in mTOR and an mTORC2-specific nucleotide binding 
      site in Rictor, which also forms a zinc finger. Structural and biochemical 
      analyses suggest that InsP6 and nucleotide binding do not control mTORC2 activity 
      directly but rather have roles in folding or ternary interactions. These insights 
      provide a firm basis for studying mTORC2 signaling and for developing 
      mTORC2-specific inhibitors.
CI  - Copyright (c) 2020 The Authors, some rights reserved; exclusive licensee American 
      Association for the Advancement of Science. No claim to original U.S. Government 
      Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 
      (CC BY-NC).
FAU - Scaiola, Alain
AU  - Scaiola A
AUID- ORCID: 0000-0003-3233-3910
AD  - Institute for Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland.
FAU - Mangia, Francesca
AU  - Mangia F
AUID- ORCID: 0000-0001-5430-397X
AD  - Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, 
      Switzerland.
FAU - Imseng, Stefan
AU  - Imseng S
AD  - Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, 
      Switzerland.
FAU - Boehringer, Daniel
AU  - Boehringer D
AUID- ORCID: 0000-0002-6666-8447
AD  - Cryo-EM Knowledge Hub, ETH Zurich, 8093 Zurich, Switzerland.
FAU - Berneiser, Karolin
AU  - Berneiser K
AUID- ORCID: 0000-0002-0963-8559
AD  - Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, 
      Switzerland.
FAU - Shimobayashi, Mitsugu
AU  - Shimobayashi M
AD  - Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, 
      Switzerland.
FAU - Stuttfeld, Edward
AU  - Stuttfeld E
AD  - Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, 
      Switzerland.
FAU - Hall, Michael N
AU  - Hall MN
AD  - Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, 
      Switzerland.
FAU - Ban, Nenad
AU  - Ban N
AUID- ORCID: 0000-0002-9527-210X
AD  - Institute for Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland. 
      ban@mol.biol.ethz.ch timm.maier@unibas.ch.
FAU - Maier, Timm
AU  - Maier T
AUID- ORCID: 0000-0002-7459-1363
AD  - Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, 
      Switzerland. ban@mol.biol.ethz.ch timm.maier@unibas.ch.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201106
PL  - United States
TA  - Sci Adv
JT  - Science advances
JID - 101653440
RN  - 0 (Carrier Proteins)
RN  - 0 (Nucleotides)
RN  - 0 (Rapamycin-Insensitive Companion of mTOR Protein)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - *Carrier Proteins/metabolism
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 2/metabolism
MH  - Nucleotides/metabolism
MH  - Rapamycin-Insensitive Companion of mTOR Protein/metabolism
MH  - *TOR Serine-Threonine Kinases/metabolism
MH  - Transcription Factors/metabolism
PMC - PMC7673708
EDAT- 2020/11/08 06:00
MHDA- 2022/04/15 06:00
PMCR- 2020/11/06
CRDT- 2020/11/07 05:28
PHST- 2020/04/07 00:00 [received]
PHST- 2020/09/22 00:00 [accepted]
PHST- 2020/11/07 05:28 [entrez]
PHST- 2020/11/08 06:00 [pubmed]
PHST- 2022/04/15 06:00 [medline]
PHST- 2020/11/06 00:00 [pmc-release]
AID - 6/45/eabc1251 [pii]
AID - abc1251 [pii]
AID - 10.1126/sciadv.abc1251 [doi]
PST - epublish
SO  - Sci Adv. 2020 Nov 6;6(45):eabc1251. doi: 10.1126/sciadv.abc1251. Print 2020 Nov.