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dc.contributor.advisorKuang Shenen_US
dc.contributor.authorEgri, Shawn B.
dc.date.accessioned2023-04-07T12:44:28Z
dc.date.available2023-04-07T12:44:28Z
dc.date.issued2023-03-10
dc.identifier.doi10.13028/pbfs-dm43en_US
dc.identifier.urihttp://hdl.handle.net/20.500.14038/51921
dc.description.abstractIn order to initiate cellular growth, a cell must weigh its nutrient availability against its anabolic needs. A critical pathway responsible for this process is the mechanistic target of rapamycin complex 1 (mTORC1) pathway. mTORC1 is a serine threonine protein kinase complex that will phosphorylate its downstream substrates in order to promote anabolic reactions. mTORC1 activity is dependent upon the Rag GTPase heterodimer. In the presence of amino acids, the Rags will activate mTORC1 by promoting its translocation to the lysosomal surface. In contrast, amino acid withdrawal results in mTORC1 inactivation. In order to ensure faithful mTORC1 signaling, the nucleotide loading state of the Rag GTPase is tightly regulated. In this thesis, we combine biochemical and biophysical approaches to investigate the molecular mechanism of how the nucleotide loading state of the Rag GTPase subunits are regulated. First, we characterized a conserved interdomain hydrogen bond within the Rag GTPases that is responsible for maintaining the GDP-bound state of the subunits. Elimination of this hydrogen bond abolishes the ability of the Rag GTPase to maintain its functional state, resulting in dysregulated mTORC1 signaling. Second, we utilize cryo-EM to describe the molecular mechanism of how GATOR1, a potent negative regulator of the mTORC1 pathway, modulates the nucleotide loading state of the Rag subunits in response to nutrient deprivation. These results reveal the molecular details of how the Rag GTPases are regulated in response to changes in amino acid availability, and furthermore how disruptions to those mechanisms can lead to dysregulation of the mTORC1 signaling pathway.en_US
dc.language.isoen_USen_US
dc.publisherUMass Chan Medical Schoolen_US
dc.rightsCopyright © 2023 Egrien_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.subjectGTPase-Activating Proteinen_US
dc.subjectBiochemistryen_US
dc.subjectStructural Biologyen_US
dc.subjectCell Growthen_US
dc.subjectmTORC1en_US
dc.subjectNutrient Sensingen_US
dc.subjectSignalingen_US
dc.subjectGTPaseen_US
dc.subjectCanceren_US
dc.subjectBiologyen_US
dc.subjectSingle Particle Cryo-EMen_US
dc.titleMolecular Mechanisms of Amino Acid Sensing Upstream of mTORC1en_US
dc.typeDoctoral Dissertationen_US
atmire.contributor.authoremailshawn.egri@umassmed.eduen_US
dc.contributor.departmentProgram in Molecular Medicineen_US
dc.description.thesisprogramInterdisciplinaryen_US
dc.identifier.orcid0000-0002-8832-0601en_US


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