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- PDB-9dx2: Human GATOR2 complex - CASTOR1 bound state -

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Basic information

Entry
Database: PDB / ID: 9dx2
TitleHuman GATOR2 complex - CASTOR1 bound state
Components
  • Cytosolic arginine sensor for mTORC1 subunit 1
  • GATOR2 complex protein MIOS
  • GATOR2 complex protein WDR24
  • Nucleoporin SEH1
  • Protein SEC13 homolog
KeywordsSIGNALING PROTEIN / nutrient sensor / mTORC1 pathway / stress-responsive protein
Function / homology
Function and homology information


cellular response to L-arginine / molecular sensor activity / Amino acids regulate mTORC1 / arginine binding / negative regulation of TORC1 signaling / positive regulation of TORC1 signaling / cellular response to amino acid starvation / protein sequestering activity / identical protein binding / cytosol
Similarity search - Function
CASTOR family / CASTOR1, N-terminal / : / Cytosolic arginine sensor for mTORC1 subunit 1 N-terminal domain / Cytosolic arginine sensor for mTORC1 subunit 1/2, ACT-like / : / CASTOR, ACT domain / ACT domain / ACT-like domain
Similarity search - Domain/homology
Cytosolic arginine sensor for mTORC1 subunit 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsWranik, M. / Rogala, K.B.
Funding support United States, 5items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM150935 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R00 CA255926 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)P30 CA124435 United States
Department of Defense (DOD, United States)CA220856 United States
Lustgarten Foundation1156790 United States
CitationJournal: Nature / Year: 2025
Title: Structural basis for the dynamic regulation of mTORC1 by amino acids.
Authors: Max L Valenstein / Maximilian Wranik / Pranav V Lalgudi / Karen Y Linde-Garelli / Yuri Choi / Raghu R Chivukula / David M Sabatini / Kacper B Rogala /
Abstract: The mechanistic target of rapamycin complex 1 (mTORC1) anchors a conserved signalling pathway that regulates growth in response to nutrient availability. Amino acids activate mTORC1 through the Rag ...The mechanistic target of rapamycin complex 1 (mTORC1) anchors a conserved signalling pathway that regulates growth in response to nutrient availability. Amino acids activate mTORC1 through the Rag GTPases, which are regulated by GATOR, a supercomplex consisting of GATOR1, KICSTOR and the nutrient-sensing hub GATOR2 (refs. ). GATOR2 forms an octagonal cage, with its distinct WD40 domain β-propellers interacting with GATOR1 and the leucine sensors Sestrin1 and Sestrin2 (SESN1 and SESN2) and the arginine sensor CASTOR1 (ref. ). The mechanisms through which these sensors regulate GATOR2 and how they detach from it upon binding their cognate amino acids remain unknown. Here, using cryo-electron microscopy, we determined the structures of a stabilized GATOR2 bound to either Sestrin2 or CASTOR1. The sensors occupy distinct and non-overlapping binding sites, disruption of which selectively impairs the ability of mTORC1 to sense individual amino acids. We also resolved the apo (leucine-free) structure of Sestrin2 and characterized the amino acid-induced structural rearrangements within Sestrin2 and CASTOR1 that trigger their dissociation from GATOR2. Binding of either sensor restricts the dynamic WDR24 β-propeller of GATOR2, a domain essential for nutrient-dependent mTORC1 activation. These findings reveal the allosteric mechanisms that convey amino acid sufficiency to GATOR2 and the ensuing structural changes that lead to mTORC1 activation.
History
DepositionOct 10, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 20, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GATOR2 complex protein MIOS
B: GATOR2 complex protein MIOS
C: Nucleoporin SEH1
D: Protein SEC13 homolog
E: Cytosolic arginine sensor for mTORC1 subunit 1
F: Cytosolic arginine sensor for mTORC1 subunit 1
G: Cytosolic arginine sensor for mTORC1 subunit 1
H: GATOR2 complex protein WDR24


Theoretical massNumber of molelcules
Total (without water)529,1908
Polymers529,1908
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein GATOR2 complex protein MIOS


Mass: 88740.953 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#2: Protein Nucleoporin SEH1


Mass: 63832.641 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#3: Protein Protein SEC13 homolog


Mass: 60774.332 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
#4: Protein Cytosolic arginine sensor for mTORC1 subunit 1 / Cellular arginine sensor for mTORC1 protein 1 / GATS-like protein 3


Mass: 36222.164 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASTOR1, GATSL3 / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: Q8WTX7
#5: Protein GATOR2 complex protein WDR24


Mass: 118434.242 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human GATOR2 complex bound to CASTOR1 / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightValue: 1.3 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293F
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: 4D-STEM / Nominal defocus max: 2100 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 69.44 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1Topaz0.2.5particle selection
13cryoSPARC4.53D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 865410 / Symmetry type: POINT

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