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Frontiers in Biology

Front. Biol.    2018, Vol. 13 Issue (4) : 237-262     https://doi.org/10.1007/s11515-018-1501-7
REVIEW
Signal integration in the (m)TORC1 growth pathway
Kailash Ramlaul, Christopher H. S. Aylett()
Section of Structural Biology, Department of Medicine, Imperial College London, SW7 2AZ, UK
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Abstract

BACKGROUND: The protein kinase Target Of Rapamycin (TOR) is a nexus for the regulation of eukaryotic cell growth. TOR assembles into one of two distinct signalling complexes, TOR complex 1 (TORC1) and TORC2 (mTORC1/2 in mammals), with a set of largely non-overlapping protein partners. (m)TORC1 activation occurs in response to a series of stimuli relevant to cell growth, including nutrient availability, growth factor signals and stress, and regulates much of the cell’s biosynthetic activity, from proteins to lipids, and recycling through autophagy. mTORC1 regulation is of great therapeutic significance, since in humans many of these signalling complexes, alongside subunits of mTORC1 itself, are implicated in a wide variety of pathophysiologies, including multiple types of cancer, neurological disorders, neurodegenerative diseases and metabolic disorders including diabetes.

METHODOLOGY: Recent years have seen numerous structures determined of (m)TOR, which have provided mechanistic insight into (m)TORC1 activation in particular, however the integration of cellular signals occurs upstream of the kinase and remains incompletely understood. Here we have collected and analysed in detail as many as possible of the molecular and structural studies which have shed light on (m)TORC1 repression, activation and signal integration.

CONCLUSIONS: A molecular understanding of this signal integration pathway is required to understand how (m)TORC1 activation is reconciled with the many diverse and contradictory stimuli affecting cell growth. We discuss the current level of molecular understanding of the upstream components of the (m)TORC1 signalling pathway, recent progress on this key biochemical frontier, and the future studies necessary to establish a mechanistic understanding of this master-switch for eukaryotic cell growth.

Keywords mTORC1      nutrient sensing      GATOR complex      TSC complex      Rag GTPases      Rheb     
Corresponding Author(s): Christopher H. S. Aylett   
Online First Date: 26 July 2018    Issue Date: 10 September 2018
 Cite this article:   
Kailash Ramlaul,Christopher H. S. Aylett. Signal integration in the (m)TORC1 growth pathway[J]. Front. Biol., 2018, 13(4): 237-262.
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http://journal.hep.com.cn/fib/EN/10.1007/s11515-018-1501-7
http://journal.hep.com.cn/fib/EN/Y2018/V13/I4/237
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Fig.1  Schematic of mTORC1 regulation in response to multiple stimuli. In the absence of the appropriate signals, mTORC1 is not localized to the lysosome by RagA/B-RagC/D and therefore not allosterically activated by Rheb. Inhibitory GAPs for the RagA/B and Rheb GTPases – GATOR1 and TSCC, respectively – act on their targets, while FLCN-FNIP activates RagC/D. In the presence of amino acids and key metabolites, SESN2 and CASTOR1 dissociate from GATOR2, enabling it to inhibit GATOR1 through an as-yet incompletely described mechanism, while SAMTOR dissociates from GATOR1-KICSTOR and may enable recognition of GATOR1 by GATOR2. In the absence of external stresses, such as DNA damage, low cellular energy status and reactive oxygen species production, as well as positive growth factor signaling, TSCC-mediated Rheb inhibition is relieved by posttranslational modifications of the integrator complex, which likely lead to dispersion of TSCC from the lysosome surface. Both the Rag heterodimer and Rheb GTPases can now cooperatively activate mTORC1 to stimulate biogenesis.
Fig.2  Structural biology of the nutrient sensors SESN2, CASTOR1, and SAMTOR. A. Domain organization of SESN2 and CASTOR1 and predicted domain organization of SAMTOR. Black and gray outlines represent structurally resolved or predicted regions, respectively, while colored and gray bars reflect specific features with known or putative functions, respectively. B. Crystal structure of leucine-bound SESN2 (PDB ID: 5DJ4), with bound leucine shown as cyan in stick representation. Leucine- and GATOR2-interacting residues are shown in teal and purple respectively, as highlighted in A. C. Leucine binding pocket of SESN2, as inset in B. Polar contacts are indicated by blue dashed lines, and hydrophobic interactions by yellow. D. Crystal structures of the arginine-bound, and apo, CASTOR1 homodimer (Arg-bound PDB ID: 5I2C; apo: 5GT8), with bound arginine shown as light green in stick representation. Arginine- and GATOR2-interacting residues are shown in green and purple respectively, as shown in A. E. Arginine binding pocket of CASTOR1, as inset in D. Polar contacts are indicated by bright green dashed lines. The loop which closes over the CASTOR1 binding pocket has been omitted for clarity between residues 269-276, indicated by maroon diamonds. F. Comparison of ACT4 residues 270-280 between the arginine-bound and apo CASTOR1, which form a loop over the bound arginine. Residues 275-279 are unobserved in the apo CASTOR1 crystal structure, indicating disorder.
Fig.3  Structural biology of the GATOR1 complex. (A) Domain organization of DEPDC5, NPRL2 and NPRL3. The dark red bar indicates the region of the DEPDC5 SHEN domain which interacts with RagA. (B) Cryo-electron microscopy structure of the mammalian GATOR1-RagA-RagC complex (PDB ID: 6CES; EMDB: EMD-7464). (C) Focused view of the DEPDC5SHEN-RagAGTPase domain interaction, highlighting the end-to-end β-strand interaction of the two domains and its proximity to the RagAGTPase nucleotide binding pocket. The RagA P loop, switch I and II regions are colored pale green. Bound GTP is shown as light green in stick representation.
Fig.4  Structural biology of the small GTPases Rag and the Ragulator complex. (A) Domain organization of the Rag GTPases and Ragulator complex components LAMTOR1-5. Pale green lines under RagA indicate, from N- to C terminus, the P-loop (residues 14-21), switch I (residues 39-45) and switch II (residues 60-67) regions. Pink lines under RagC similarly indicate the P-loop (residues 68-75), switch I (residues 91-99) and switch II (residues 114-122) regions. The brown bar at the LAMTOR1 N terminus indicates the palmitoylation and myristoylation motifs, while colored bars reflect the regions of interaction with other Ragulator-Rag components, colored according to the interacting proteins. (B) Crystal structure of Ragulator in complex with the Rag GTPase roadblock domain heterodimer (PDB ID: 6EHP). (C) Structure of the Rag GTPase heterodimer from the cryo-EM structure of the GATOR1-Rag GTPase complex (PDB ID: 6CES; EMDB: EMD-7464). RagA-bound GTP is shown as light green in stick representation. The P loop, switch I and II regions of RagA and RagC are colored as highlighted in A. (D) Comparison of the crystal structures of Gtr1GMPPNP-Gtr2GMPPNP (PDB ID: 3R7W) and Gtr1GTP-Gtr2GDP (PDB ID: 4ARZ), highlighting the conformational change of the Gtr2 switch I region. E. Gtr1-Gtr2 GTPase domain interface, as inset in D. Gtr1 residues R36 and R37 make direct contacts with the neighboring Gtr2 nucleotide binding pocket and the bound GDP itself. Polar contacts are indicated by dark gray dashed lines.
Fig.5  Structural biology and predicted domains of TSCC. (A) Predicted domain organization of TSC1, TSC2 and TBC1D7. Black and black-dashed outlines indicate structurally resolved proteins or fragments, respectively, while gray outlines represent predicted regions. Grey bars reflect specific features with putative functions. The crimson bar in the TSC1 coiled-coil region denotes a TSC2 interaction site. Similarly, the light orange bar in the TSC2 α-solenoid denotes a TSC1-interacting region. The pink bar in TBC1D7 represents the TSC1-interacting helix. (B) Crystal structure of the S. pombe TSC1 core domain monomer, alongside the decamer observed in each crystal form (PDB ID: 4KK0). (C) Crystal structure of the C. thermophilum TSC2 N-terminal α-solenoid fragment (PDB ID: 5HIU). (D) Crystal structure of the deposited, but as-yet unpublished, TBC1D7 crystal structure (PDB ID: 3QWL). (E) Crystal structure of a TBC1D7-TSC1 coiled coil complex (PDB ID: 4Z6Y), indicating a dimer-of-dimers structure. (F) Crystal structure of TBC1D7-TSC1 coiled coil complex (PDB ID: 5EJC), indicating a helical-bundle architecture formed between dimerization of two TSC1 coiled coil fragments and one TBC1D7 molecule. (G) Superposition of the TBC1D7-TSC1 coiled coil complex structures, highlighting the similarity in binding conformation of the two different TSC1 coil fragments. TSC1-interacting residues are shown in pink, as highlighted in A, while TBC1D7-interacting residues are colored per complex.
Fig.6  Structural biology of the small GTPase Rheb and the Rheb-dependent activation of mTORC1. (A) Domain organization of Rheb. Olive green lines indicate, from N- to C terminus, the P-loop (residues 12-20), switch I (residues 33-41) and switch II (residues 63-79) regions. (B) Crystal structure of GTP-bound Rheb (PDB ID: 1XTS), with bound GTP shown as light green in stick representation. The P loop, switch I and II regions are shown in olive green, as highlighted in A. (C) Focused view of the nucleotide binding pocket, highlighting the conformational difference between key GTP binding residue Y35 between the GDP- and GTP-bound states. (D) Comparison of the cryo-EM structures of mTORC1 alone (top; PDB ID: 6BCX; EMDB: EMD-7087) and mTORC1-Rheb (bottom; PDB ID: EMD-7086). Major conformational movements which occur upon Rheb binding, such as the N-HEAT rotation and kinase N-lobe compaction, are indicated by arrows. The mTOR kinase active sites are shown as insets in each, with the Mg2+ -coordinating residues N2343 and D2357, and catalytic residue H2340, shown. Interatomic distances labeled in Å indicate that in Rheb-bound mTORC1 these key residues shift by<1 Å toward the bound ATP.
Fig.7  Wider regulation of eukaryotic cell metabolism by mTORC1. Besides the well-characterized regulation of protein synthesis and autophagy by mTORC1, mTOR also forms a plasma membrane-localized, functionally segregated and rapamycin-insensitive complex called mTORC2, which controls cytoskeletal organization pathways and coordinates cell survival with cellular metabolism. mTORC2 is also a key activator of protein kinase Akt, which inhibits TSCC and therefore activates mTORC1 through Rheb. On the lysosome, the Ragulator complex interacts with several lysosomally-localized proteins, including the v-ATPase, SLC38A9, NPC1 and BORC complex, coordinating wider metabolism and lysosomal biogenesis and positioning to mTORC1 signaling. Additionally, the FLCN-FNIP complex also regulates lysosome positioning through interaction with Rab-RILP complexes. The GATOR2 complex interchanges subunits with the NPC and COPII vesicle coat, and alongside KICSTOR, which also features similar architectures, may have roles in lysosome-endosome and/or lysosome-autophagosome tethering and fusion. As recently determined, GATOR1 exhibits two modes of interaction with RagA/B and this interplay may endow the Rag signaling axis with unique properties. Finally, the Rag and Rheb GTPases both feature GAPs, and there is evidence supporting the role of Ragulator as a RagA/B GEF, however GEFs have not been conclusively identified for RagC/D or Rheb. The Rheb-GEF may localize to the Golgi, which is postulated to be the site of Rheb activation.
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