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Structural Proteomics Applied to the Study of Tyreoid Hormone Receptors with Coactivators and Ligands by Mass Spectrometry

Grant number: 13/04608-3
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): June 01, 2013
Effective date (End): May 31, 2015
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Principal Investigator:Fabio Cesar Gozzo
Grantee:Adriana Pianaro
Home Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Intracellular communication precedes detection and response activities of small signal molecules by specific proteins known as receptors. The signal transduction in these receptors is only understood by the study of domains and functions, besides the sites of interactions with activating or inhibitory molecules (coactivators and correpressores, respectively), and especially with ligands that trigger the transcription process. Among the various nuclear receptors are the thyroid hormone receptors (TRs) that are important to body's specific mechanisms, for example, in the lipid and carbohydrate metabolism. Disorders associated to interactions of TRs with hormones (T3 and T4) secreted by the thyroid glands originate diseases that affect a greater number of people in the world each year, for example, hyperthyroidism and hypothyroidism, so understanding how the TRs interact with these hormones and how are activated is relevant to combat these disorders. Therefore, this project aims to map the conformational dynamics of TR² complexs with coactivators and ligands and determine the three-dimensional structures of these protein-protein interactions via cross-linking and exchange of hydrogen/deuterium methods by mass spectrometry. This could map the structural differences of the connection mode of TR² with ligands and coactivators and will help in the understanding of the receptor activation. In future, this study could trigger the design of new drugs that activate or inhibit the action of TRs, which will help in the treatment of various diseases related to the thyroid.