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Caracterização estrutural e funcional de subunidades do complexo Ragulator, um regulador da sinalização por aminoácidos na via mTORC1

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Nadia Rasheed
Total Authors: 1
Document type: Doctoral Thesis
Institution: Universidade Estadual de Campinas, Instituto de Biologia
Defense date:
Advisor: Juliana Helena Costa Smetana

The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase, which functions as a cellular hub for growth and metabolic activities. mTOR exists in two complexes mTORC1 and mTORC2. mTORC1 responds to a variety of signals including growth factors, hormones, cytokines, glucose, energy and amino acids. Amino acids signaling through mTORC1 depends on a family of small Ras-related GTP-binding protein. Rag GTPases are activated by a pentameric complex named Ragulator. Ragulator complex has recently been identified as guanine exchange factor (GEF) for the Rag GTPases. Several studies have indicated the importance of Ragulator complex for the activation of mTORC1 through amino acid signalling. The complex consists of MP1, p14, p18, HBXIP and C7orf59. Here we present the crystal structure of C7orf59-HBXIP that displays roadblock domain like MP1-p14. Surprisingly, the N-terminal region of C7orf59 appeared as an unstructured loop, which is a completely new information. The presence of flexible N-terminal reminds of the Ego2 subunit of Ego complex in yeast. Mutagenesis results led us to unveil the initial findings of a possible regulatory mechanism for mTORC1 activation involving PKA and Ragulator complex subunits. Upon treatment with PKA modulators, there is clear change in the binding pattern of p18 and HBXIP with C7orf59. Such findings have opened a new way of controlling mTORC1 activity especially in pathological conditions. We have also proposed a potential interface of p18 with C7orf59 and MP1-p14 through stop codon mutants and crosslink data. The observed data revealed a lot of information that would be useful for future studies on Ragulator complex and its characterization as potential target to control mTORC1 in various disease conditions (AU)

FAPESP's process: 14/12445-0 - Structural characterization of the ragulator complex, a mediator of the amino acid signaling to mTORC1
Grantee:Juliana Helena Costa Smetana
Support type: Regular Research Grants