Cellular metabolism comprises biochemical pathways that either convert or consume energy and that are essential to the cell's survival, growth and proliferation. Key metabolic pathways involving carbohydrates, amino acids, fatty acids, and other major nutrients are essential for energy homeostasis and macromolecular synthesis in the cell. In mammalian cells, the target of rapamycin complex-1 (mTORC1) is the master regulator of cellular metabolic processes, and it ultimately controls the cell's growth and proliferation. mTORC1 is activated by amino acids through its relocalization from the cytosol to the lysosomal surface, where it is phosphorylated. It is recruited to the lysosomal surface by the RagB-RagC complex, a GTPase heterodimer that itself docks on the pentameric Ragulator complex. mTORC1's interaction with Rag depends on its nucleotide-binding state. When RagB is bound to GDP, the GTPase heterodimer does not interact with mTORC1. Upon AA activation, Ragulator acts as a guanine exchange factor (GEF) to RagB, helping it to change from the GDP-bound to a GTP-bound state. The GTPase heterodimer that contains RagB.GTP then binds to mTORC1 to recruit it to the lysosome where is it activated. Therefore, questions on how Ragulator functions as a platform for Rag docking, how Rag changes from the inactive RagB.GDP-RagC state to the active RagB.GTP-RagC state, and how Ragulator facilitates the nucleotide change, are central for the understanding of the molecular mechanism of mTORC1 activation. In this project, we aim to study the mechanism of mTORC1 recruitment to the lysosome via Ragulator-Rag using a combination of structural and biochemical approaches. This will yield a better understanding of cell growth as well as pathogenesis of aging, diabetes, obesity and various types of cancer.
In mammalian cells, the target of rapamycin complex-1 (mTORC1) is the master regulator of cellular metabolic processes, and it ultimately controls the cell's growth and proliferation. mTORC1 is activated by amino acids through its relocalization to the lysosomal surface by the Ragulator-Rag complex. In this project, we aim to study the mechanism of mTORC1 recruitment to the lysosome via Ragulator-Rag using a combination of structural and biochemical approaches. This will yield a better understanding of cell growth as well as pathogenesis of aging, diabetes, obesity and various types of cancer.
