Journal
SCIENCE
Volume 351, Issue 6268, Pages 48-52Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaa3870
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Funding
- ETH Zurich postdoctoral fellowship
- European Molecular Biology Organization
- People Program (Marie Curie Actions
- REA grant) [328159]
- European Research Council
- Swiss National Science Foundation via the National Centre of Excellence in RNA and Disease [138262, R'Equip 145023]
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Target of rapamycin (TOR), a conserved protein kinase and central controller of cell growth, functions in two structurally and functionally distinct complexes: TORC1 and TORC2. Dysregulation of mammalian TOR (mTOR) signaling is implicated in pathologies that include diabetes, cancer, and neurodegeneration. We resolved the architecture of human mTORC1 (mTOR with subunits Raptor and mLST8) bound to FK506 binding protein (FKBP)-rapamycin, by combining cryo-electron microscopy at 5.9 angstrom resolution with crystallographic studies of Chaetomium thermophilum Raptor at 4.3 angstromresolution. The structure explains how FKBP-rapamycin and architectural elements of mTORC1 limit access to the recessed active site. Consistent with a role in substrate recognition and delivery, the conserved amino-terminal domain of Raptor is juxtaposed to the kinase active site.
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