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Structural basis for mTORC1 regulation by the CASTOR1-GATOR2 complex.

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Arginine levels regulate mTORC1, a key metabolism controller. The study reveals how arginine sensor CASTOR1 binding to GATOR2 disinhibits GATOR1, activating mTORC1 under low arginine conditions.

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Area of Science:

  • Cellular metabolism
  • Molecular biology
  • Biochemistry

Background:

  • Mechanistic target of rapamycin complex 1 (mTORC1) regulates metabolism in response to nutrients.
  • Amino acids control mTORC1 localization and activation at the lysosome via Rag GTPases.
  • GATOR1, a GTPase activating protein complex, inactivates mTORC1 under low nutrient conditions by promoting GTP hydrolysis on RagA/B.

Purpose of the Study:

  • To elucidate the structural mechanism by which the arginine sensor CASTOR1 interacts with the GATOR2 complex.
  • To understand how this interaction disinhibits GATOR1, thereby activating mTORC1 under conditions of low cytosolic arginine.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was used to determine the structure of GATOR2 bound to apo-CASTOR1.
  • Structural analysis focused on the interfaces between CASTOR1 and GATOR2 components.

Main Results:

  • The cryo-EM structure revealed that two MIOS WD40 domain β-propellers of GATOR2 bind to a single CASTOR1 homodimer.
  • Each GATOR2 propeller interacts with a distinct MIOS-binding interface (MBI) on CASTOR1, located away from the arginine-binding pocket.
  • Arginine binding induces a conformational change in CASTOR1, leading to loop ordering that obstructs the MBI, disrupting GATOR2 binding and activating mTORC1.

Conclusions:

  • The study provides a structural basis for how arginine levels control mTORC1 signaling through the CASTOR1-GATOR2-GATOR1 axis.
  • This mechanism highlights the precise molecular regulation of cellular metabolism by nutrient availability.