Researchers Present Definitive Molecular Structure of mTORC1

In situations of severe nutrient deprivation mTOR prevents protein synthesis so that the cell can conserve energy. However, in cancer cells the mTOR pathway does not function correctly and signals tumor cells to grow, divide, undergo metastasis, and invade new, healthy tissues. Functionally, mTOR is the catalytic subunit of two structurally distinct complexes: mTORC1 and mTORC2. Both complexes localize to different subcellular compartments, thus affecting their activation and function.

MTOR complex 1 (mTORC1) is composed of the proteins mTOR, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8), and the non-core components PRAS40 and DEPTOR. This complex functions as a nutrient/energy/redox sensor and controls protein synthesis. The activity of mTORC1 is stimulated by insulin, growth factors, serum, phosphatidic acid, amino acids (particularly leucine), and oxidative stress.

The extremely large size of the mTORC1 complex has so far prevented researchers from being able to resolve its structure. However, in a study published in the December 17, 2015, online edition of the journal Science, investigators from the University of Basel (Switzerland) described combining cryo-electron microscopy at 5.9 angstrom [1 angstrom = 0.1 nm] resolution with crystallographic studies of Chaetomium thermophilum Raptor at 4.3 angstrom resolution.

The structural details established during this study served to explain how FKBP (FK506 binding protein)-rapamycin and architectural elements of mTORC1 limited access to a recessed active site in the complex. Consistent with a role in substrate recognition and delivery, the conserved N-terminal domain of Raptor was juxtaposed with the kinase active site.

"The partner proteins of mTOR have already been identified in earlier biochemical studies", said senior author Dr. Timm Maier, professor of structural biology at the University of Basel. "However, it has remained unclear how the proteins interact precisely. But it does not make sense to examine the individual components alone, as the interactions of all the proteins in the complex are critical for its function. The whole is much more than the sum of its parts. Although there is much known about mTORC1, our study revealed surprising new insight. The architecture of this huge protein complex is quite exceptional. We could determine the precise interaction sites of the partner proteins and how they are arranged, and thus elucidate the function of the individual partners."

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