Regulation of mTOR by Nutrients
Final rept. 1 Jul 2009-30 Jun 2012
CALIFORNIA UNIV SAN DIEGO LA JOLLA
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The mammalian target of rapamycin complex 1, mTORC1, is constitutively activated in TSC 1 or TSC2 mutant cells and contributes to the pathogenesis of TSC. Rapamycin, which is a potent inhibitor of TORC1, is in clinical trials for TSC and related diseases. Amino acids are key signals for mTORC1 activation. We have shown that the Rag family GTPases play a critical role in mTORC1 activation in response to amino acid stimulation. Gtr1 and Gtr2 are Rag homologs in yeast and they are also involved amino acid-induced TORC1 activation in yeast. We have solved the three dimensional structure of Gtr1-Gtr2 complex. This is the first GTPase dimmer structure ever to be solved. Our structure provides key molecular insights into the mechanism of Rag GTPase interaction with raptor and the regulators, which consists of MP1P14P18 complex. Remarkably, the C-terminal diner structure of Gtr1-Gtr2 is highly similar to the structure of P14MP1 dimmer although there is not primarily sequence homology between Gtr and P14MP1. Our study also reveals the molecular basis how Rag is recruited to the lysosomes by regulators and the mechanism of mTORC1 activation by amino acids.
- Medicine and Medical Research
- Food, Food Service and Nutrition