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.

Structural insights of mTOR complex 1

“…According to the current architecture, Raptor binding further restricts the access to the active site, resulting in the enclosure of the active site cleft from all directions and reduction of its width to ~20 Å [6]. Moreover, binding of FKBP12-rapamycin complex to the FRB domain of mTORC1 further reduces the active site cleft to ~10 Å [6].…”

“…In a recent paper published in Science, the architecture of human mTORC1 was revealed by high-resolution cryo-EM [6]. The authors purified mTORC1 complex (human mTOR together with Raptor, and mLST8) bound to FKBP12-rapamycin from insect cells.…”

“…Interestingly, the N-terminus of mTOR, which was not resolved in previous study [5], contains two α-helical solenoids. The larger section is a highly curved super-helix, which is named the "horn", while the smaller region adopts a relatively linear arrangement and is referred to as the "bridge" [6]. Both sections are predominantly exposed to the environment, indicating a potential role in binding mTOR regulators.…”

“…Both sections are predominantly exposed to the environment, indicating a potential role in binding mTOR regulators. In addition, the horn and bridge HEAT domains pack against one another, and the first HEAT repeat of the horn region interlocks with the adjacent mTOR FAT domain, through which the two mTOR subunits forms a dimer independent of Raptor [6]. Another interesting observation is that the conformation of the kinase domain appears unaffected by dimerization, suggesting that the regulation of mTORC1 may be mainly through controlling substrate access to the active site.…”

“…Raptor interacts with mTOR through an α-solenoid stack formed between the horn and bridge domains of mTOR via the Raptor armadillo domain [6]. It is proposed that Raptor stabilizes the N-terminal region of mTOR by providing roughly twothirds of the interaction surface with HEAT domains.…”