Architecture of human mTOR complex 1

  title={Architecture of human mTOR complex 1},
  author={Christopher H. S. Aylett and Evelyn Sauer and Stefan Imseng and Daniel Boehringer and Michael N. Hall and Nenad Ban and Timm Maier},
  pages={48 - 52}
From sensing leucine to metabolic control The mTORC1 protein kinase complex plays central roles in regulating cell growth and metabolism and is implicated in common human diseases such as diabetes and cancer. The level of the amino acid leucine tells an organism a lot about its physiological state, including how much food is available, how much insulin is going to be needed, and whether new muscle mass can be made (see the Perspective by Buel and Blenis). Wolfson et al. identified a biochemical… 
Mechanisms of amino acid sensing by the mTORC1 pathway
These structures have paved the way for the development of novel compounds targeting mTORC1 through the Sestrin2 and CASTOR1 amino acid-binding pockets, which may have important clinical implications in the context of cancer, diabetes, neurological disorders, and longevity.
Sensors for the mTORC1 pathway regulated by amino acids
Recently, several sensors of leucine, arginine, and S-adenosylmethionine for the amino acid-stimulated mTORC1 pathway have been coming to light and characterization of these sensors is requisite for understanding how cells adjust amino acid sensing pathways to their different needs.
Regulation of mTORC1-Dependent Growth Signaling by Lysosomal Cholesterol
Cholesterol, an essential lipid for cellular growth, is identified as a nutrient input that drives mTORC1 recruitment and activation at the lysosomal surface and is suggested to contribute to the metabolic derangement observed in Niemann-Pick Type C (NPC) disease in humans.
Cryo-EM insight into the structure of MTOR complex 1 and its interactions with Rheb and substrates
A deep understanding is sought of how MTORC1 interacts with and phosphorylates its best-known substrates—the eIF-4E binding protein/4E-BP, the p70 S6 kinase/S6K1B, and PRAS40/AKT1S1—and how this is inhibited by rapamycin.
Regulation of human mTOR complexes by DEPTOR
The multifaceted interplay between DEPTOR and mTOR provides a basis for understanding the divergent roles of DEPTor in physiology and opens new routes for targeting the mTOR-DEPTOR interaction in disease.
Architecture of human Rag GTPase heterodimers and their complex with mTORC1
Cryo–electron microscopy and crystal structures of RagA/RagC in complex with mTORC1 show the mechanism for this locking and explain how oncogenic hotspot mutations disrupt this process.
The 3.2-Å resolution structure of human mTORC2
A 3.2-Å resolution cryo-EM reconstruction of mTORC2 reveals entangled folds of the defining Rictor and the substrate-binding SIN1 subunits, identifies the carboxyl-terminal domain of Rictsor as the source of the rapamycin insensitivity of m TORC2, and resolves mechanisms for mTORc2 regulation by complex destabilization.
Structural Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40
The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to nutrients, energy levels, and growth factors. It contains the atypical kinase mTOR and the
Regulation and metabolic functions of mTORC1 and mTORC2.
Since mTOR is an important target for cancer, aging and other metabolism-related pathologies, understanding the distinct and overlapping regulation and functions of the two mTOR complexes is vital for the development of more effective therapeutic strategies.
Lysosomal Regulation of mTORC1 by Amino Acids in Mammalian Cells
In this review, recent progress with respect to biochemical and biological findings in the regulation of mTORC1 signaling on the lysosomal membrane by amino acids is summarized.


The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1
It is found that the Rag proteins—a family of four related small guanosine triphosphatases (GTPases)—interact with mTORC1 in an amino acid–sensitive manner and are necessary for the activation of the m TORC1 pathway by amino acids.
Molecular Organization of Target of Rapamycin Complex 2*
It is demonstrated that mammalian TOR is also oligomeric, likely a TORC2-TORC2 dimer, and the architecture of TorC2 is discussed in the context of TORC 2 assembly and regulation.
mTOR kinase structure, mechanism and regulation by the rapamycin-binding domain
Co-crystal structures of a complex of truncated mTOR and mammalian lethal with SEC13 protein 8 with an ATP transition state mimic and with ATP-site inhibitors reveal an intrinsically active kinase conformation, with catalytic residues and a catalytic mechanism remarkably similar to canonical protein kinases.
Regulation of mTOR Complex 1 (mTORC1) by Raptor Ser863 and Multisite Phosphorylation*
It is reported that insulin promotes mTORC1-associated phosphorylation of raptor Ser863 via the canonical PI3K/TSC/Rheb pathway in a rapamycin-sensitive manner.
A mammalian protein targeted by G1-arresting rapamycin–receptor complex
A mammalian FKBP–rapamycin-associated protein (FRAP) is isolate whose binding to structural variants of rapamycin complexed to FK BP12 correlates with the ability of these ligands to inhibit cell-cycle progression.