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Architecture of human mTOR complex 1

Christopher H S Aylett1, Evelyn Sauer2, Stefan Imseng2

  • 1Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland.

Science (New York, N.Y.)
|December 19, 2015
PubMed

Insights

Researchers revealed the structure of the human mTORC1 complex bound to FKBP-rapamycin. This structure clarifies how the complex

Area of Science:

  • Molecular biology
  • Cellular signaling
  • Structural biology

Background:

  • Target of rapamycin (TOR) is a key regulator of cell growth, existing in two complexes: TORC1 and TORC2.
  • Dysregulated mammalian TOR (mTOR) signaling is linked to diseases like cancer, diabetes, and neurodegeneration.

Purpose of the Study:

  • To determine the high-resolution architecture of the human mTORC1 complex bound to FKBP-rapamycin.
  • To elucidate the structural mechanisms underlying mTORC1 regulation and substrate interaction.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) at 5.9 angstrom resolution.
  • Crystallographic studies of Chaetomium thermophilum Raptor at 4.3 angstrom resolution.

Main Results:

  • The study resolved the architecture of human mTORC1, including its subunits Raptor and mLST8, in complex with FKBP-rapamycin.
  • The determined structure explains how FKBP-rapamycin and mTORC1's architecture restrict access to the active site.
  • The conserved amino-terminal domain of Raptor is positioned near the kinase active site, suggesting a role in substrate recognition.

Conclusions:

  • The resolved structure provides critical insights into the regulation of mTORC1 activity.
  • Understanding mTORC1 architecture is crucial for developing therapeutic strategies targeting diseases associated with its dysregulation.

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