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Structure and function of proteins involved in amino acid-mediated regulation mTORC1 pathway


The PI3K-Akt-mTOR signaling pathway is a central axis controlling cell growth, proliferation and survival. Components of this pathway are often dysregulated in cancer. Mechanistic Target of Rapamycin (mTOR) kinase is a conserved protein that plays an essential role in regulating cell growth, integrating signals of nutrient availability, growth factors, and various types of stress. The response of the mTORC1 pathway to the presence of amino acids has been the subject of intense research in the last decade. The Ragulator complex is an important mediator of amino acid signaling that acts through Rag GTPases, functioning as a nucleotide exchange factor (GEF) for these GTPases, as well as an anchor (scaffold) on the lysosomal surface. In a previous project, we initiated the structural characterization of the Ragulator complex, formed by the proteins MP1, p14, p18, HBXIP and C7orf59, to unravel the molecular mechanism of the activation of mTOR by amino acids. In the previous project, we reconstituted the pentameric Ragulator in vitro, solved the structure of the HBXIP-C7orf59 dimer, mapped its interaction with p18 and identified a functional connection of Ragulator with the PKA kinase. This project aims to deepen and expand the results obtained previously. The objectives of the project are to investigate the mechanism of regulation of Ragulator by PKA kinase, to conduct a structural and functional comparative study of HBXIP isoforms, to refine the mapping of p18 interactions with Ragulator subunits and Rag GTPases, and to perform crystallization attempts with subcomplexes to explore the interfaces of the Rag-Ragulator complex. The expected results will be very relevant contributions in the field of mTOR research, allowing to elucidate fundamental mechanisms in the regulation of this pathway and bringing possibilities of application in the development of new compounds that modulate mTOR activity in the cell. (AU)

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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
RASHEED, NADIA; LIMA, TATIANI B.; MERCALDI, GUSTAVO F.; NASCIMENTO, ANDREY F. Z.; SILVA, ANA L. S.; RIGHETTO, GERMANNA L.; BAR-PELED, LIRON; SHEN, KUANG; SABATINI, DAVID M.; GOZZO, FABIO C.; et al. C7orf59/LAMTOR4 phosphorylation and structural flexibility modulate Ragulator assembly. FEBS OPEN BIO, v. 9, n. 9, . (17/21455-7, 14/17264-3, 14/12445-0)

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