Architecture of the human mTORC2 core complex
- University of Basel, Switzerland
- ETH Zürich, Switzerland
Abstract
The mammalian target of rapamycin (mTOR) is a key protein kinase controlling cellular metabolism and growth. It is part of the two structurally and functionally distinct multiprotein complexes mTORC1 and mTORC2. Dysregulation of mTOR occurs in diabetes, cancer and neurological disease. We report the architecture of human mTORC2 at intermediate resolution, revealing a conserved binding site for accessory proteins on mTOR and explaining the structural basis for the rapamycin insensitivity of the complex.
Data availability
-
Human mTORC2 Core Complex (C2)Publicly available at the EBI EM-3927.
-
Human mTORC2 core complex accessory factorsPublicly available at the EBI EM-3928.
Article and author information
Author details
Funding
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (51NF40_141735_NCCR)
- Nenad Ban
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030_159492)
- Michael N Hall
European Research Council (609883)
- Michael N Hall
Sir Henry Dale Fellowship (206212/Z/17/Z)
- Christopher H S Aylett
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (138262)
- Nenad Ban
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (159696)
- Timm Maier
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030B_163478)
- Nenad Ban
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Nahum Sonenberg, McGill University, Canada
Version history
- Received: October 25, 2017
- Accepted: February 8, 2018
- Accepted Manuscript published: February 9, 2018 (version 1)
- Version of Record published: March 5, 2018 (version 2)
Copyright
© 2018, Stuttfeld et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 5,075
- Page views
-
- 1,016
- Downloads
-
- 59
- Citations
Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Architecture of the human mTORC2 core complex
eLife 7:e33101.
https://doi.org/10.7554/eLife.33101
Further reading
-
- Structural Biology and Molecular Biophysics
The dimeric two-pore OSCA/TMEM63 family has recently been identified as mechanically activated ion channels. Previously, based on the unique features of the structure of OSCA1.2, we postulated the potential involvement of several structural elements in sensing membrane tension (Jojoa-Cruz et al., 2018). Interestingly, while OSCA1, 2, and 3 clades are activated by membrane stretch in cell-attached patches (i.e. they are stretch-activated channels), they differ in their ability to transduce membrane deformation induced by a blunt probe (poking). Here, in an effort to understand the domains contributing to mechanical signal transduction, we used cryo-electron microscopy to solve the structure of Arabidopsis thaliana (At) OSCA3.1, which, unlike AtOSCA1.2, only produced stretch- but not poke-activated currents in our initial characterization (Murthy et al., 2018). Mutagenesis and electrophysiological assessment of conserved and divergent putative mechanosensitive features of OSCA1.2 reveal a selective disruption of the macroscopic currents elicited by poking without considerable effects on stretch-activated currents (SAC). Our results support the involvement of the amphipathic helix and lipid-interacting residues in the membrane fenestration in the response to poking. Our findings position these two structural elements as potential sources of functional diversity within the family.
-
- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
The heterochromatin protein 1 (HP1) family is a crucial component of heterochromatin with diverse functions in gene regulation, cell cycle control, and cell differentiation. In humans, there are three paralogs, HP1α, HP1β, and HP1γ, which exhibit remarkable similarities in their domain architecture and sequence properties. Nevertheless, these paralogs display distinct behaviors in liquid-liquid phase separation (LLPS), a process linked to heterochromatin formation. Here, we employ a coarse-grained simulation framework to uncover the sequence features responsible for the observed differences in LLPS. We highlight the significance of the net charge and charge patterning along the sequence in governing paralog LLPS propensities. We also show that both highly conserved folded and less-conserved disordered domains contribute to the observed differences. Furthermore, we explore the potential co-localization of different HP1 paralogs in multicomponent assemblies and the impact of DNA on this process. Importantly, our study reveals that DNA can significantly reshape the stability of a minimal condensate formed by HP1 paralogs due to competitive interactions of HP1α with HP1β and HP1γ versus DNA. In conclusion, our work highlights the physicochemical nature of interactions that govern the distinct phase-separation behaviors of HP1 paralogs and provides a molecular framework for understanding their role in chromatin organization.
