Structural and Mechanistic Analyses of TSC1/2 and Rheb 1/2-Mediated Regulation of the mTORC Pathway
Abstract
The multiprotein mTORC1 protein kinase complex is the central component of a pathway that promotes growth in response to insulin, energy levels, and amino acids and is deregulated in common cancers. In particular, the mTOR pathway is hyperactive in Tuberous Sclerosis Complex (TSC), a mental retardation and cancer-prone syndrome affecting 1 in 6,000 people in the United States. With the long-term goal of developing anti-cancer therapeutics based on the mTORC1 regulatory mechanism, we recently found that the Rag proteins, a family of four related small GTPases, interact with mTORC1 in an amino acid sensitive manner and are necessary for the activation of the mTORC1 pathway by amino acids. The Rag proteins do not directly stimulate the kinase activity of mTORC1, but, like amino acids, promote the intracellular localization of mTOR to a compartment that also contains its activator Rheb. In addition, our structural analysis of mTORC1 generated preliminary cryo-EM reconstructions of the mTORC1 dimer and Raptor at resolutions of 25 and 30 , respectively.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 31, 2008
- Accession Number
- ADA488112
Entities
People
- David M. Sabatini
Organizations
- Whitehead Institute