title: Architecture of human mTOR complex 1.
abstract: 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 angstrom resolution. 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.
authors.affiliation: Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland.
authors.forename: Christopher H S
authors.initials: CH
authors.lastname: Aylett
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Sauer
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Imseng
authors.affiliation: Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Boehringer
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland. ban@mol.biol.ethz.ch m.hall@unibas.ch timm.maier@unibas.ch.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
authors.affiliation: Institute of Molecular Biology and Biophysics, ETH Zürich, Zürich, Switzerland. ban@mol.biol.ethz.ch m.hall@unibas.ch timm.maier@unibas.ch.
authors.forename: Nenad
authors.initials: N
authors.lastname: Ban
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland. ban@mol.biol.ethz.ch m.hall@unibas.ch timm.maier@unibas.ch.
authors.forename: Timm
authors.initials: T
authors.lastname: Maier
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry*; D020134:Catalytic Domain; D020285:Cryoelectron Microscopy; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000737:chemistry*; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D000076223:Regulatory-Associated Protein of mTOR; D013379:Substrate Specificity; D058570:TOR Serine-Threonine Kinases / Q000737:chemistry*; D022021:Tacrolimus Binding Proteins / Q000737:chemistry*; D000076242:mTOR Associated Protein, LST8 Homolog
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C555285:MLST8 protein, human; D046912:Multiprotein Complexes; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; D000076242:mTOR Associated Protein, LST8 Homolog; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D022021:Tacrolimus Binding Proteins