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Identification of the minimal binding region to glucose-6-phosphate (G6P) of the transcription factor MondoA and further structural studies

Grant number: 13/01540-9
Support type:Scholarships in Brazil - Master
Effective date (Start): May 01, 2013
Effective date (End): November 30, 2014
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Andre Luis Berteli Ambrosio
Grantee:Camila Cristina Pascoal
Home Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brasil). Campinas , SP, Brazil

Abstract

The transcription factor MondoA is a key transcriptional glucose biosensor. Originally located in the cytoplasm, MondoA accumulate in the nucleus in response to high intracellular glucose concentration in order to regulate genes involved in glucose metabolic pathways. Given the importance of this factor for glucose metabolism and its possible direct relationship with the transcription factor and oncongene Myc, it is speculated that MondoA directly cooperates with the latter in the process of metabolic adaptation of tumors. Structurally, there are five conserved regions in the amino-terminus of MondoA - the Mondo Conserved Regions (MCRI-V) - which appear to act cooperatively repressing or activating the transactivation function of MondoA in response to glucose. Recent studies show that the activation of MondoA depends on direct binding to its amino-terminus of glucose-6-phosphate (G6P), resulting from the phosphorylation of glucose by he xokinase. That would be the first confirmation of direct regulation of gene transcription by metabolic products. However, the minimal binding region to G6P of MondoA has not yet been elucidated and this is the main objective of this project. Therefore, we propose the design of a series of constructs comprising MCR regions I to V, with focus on heterologous production in bacteria for subsequent crystallization, structural resolution as well as biochemical and biophysical characterizations of these regions in complex with G6P.