mTOR_complexesProject reference: 328159
Funded under :
Structural and biophysical characterization of the human mTOR kinase and its signaling complexes
Total cost:EUR 184 709,4
EU contribution:EUR 184 709,4
Topic(s):FP7-PEOPLE-2012-IEF - Marie-Curie Action: "Intra-European fellowships for career development"
Call for proposal:FP7-PEOPLE-2012-IEFSee other projects for this call
Funding scheme:MC-IEF - Intra-European Fellowships (IEF)
Cell growth and proliferation are fundamental processes whereby organisms accumulate mass and are therefore tightly regulated. Regulation is achieved by a complex network of signaling pathways responding to various environmental cues. A crucial nutrient and energy-sensitive pathway is centered on the Serine/Threonine kinase mechanistic target of rapamycin (mTOR). In the cell, mTOR interacts with several proteins to form two multi-subunit signaling complexes: mTORC1 and mTORC2. mTORC1 responds to the intracellular energy state reflected in amino acid and oxygen levels and integrates extracellular signals from growth factors to control cell size and proliferation. mTORC2 responds to growth factors and its downstream targets regulate cell survival and cytoskeletal organization. Consequently, deregulation of mTOR signaling is directly linked to human disorders like obesity, type II diabetes or cancer, which makes mTOR a highly relevant pharmaceutical target.
Although several aspects of mTOR signaling have been understood, the lack of intermediate to high-resolution structures impairs detailed understanding of complex assembly, function and regulation. We therefore propose to determine the structures of human mTOR complexes and their subunits by X-ray crystallography. The intended research involves initial medium-throughput expression screening of mTORC1/2 subunits in bacterial and insect cells followed by a biophysical characterization of the expressed proteins. Guided by the biophysical analysis, we will establish in vitro reconstitution protocols and identify promising candidate complexes for high-throughput crystallization screening, crystal optimization and structure determination. The structures should provide first insights into the organization of human mTOR (sub)complexes and their subunits. The proposed research will be of high general impact in academic and pharmaceutical research and will therefore significantly strengthen European scientific excellence.
EU contribution: EUR 184 709,4
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