structural studies of the interaction of normal and pathological THR with corepressors

• Grant number: 16/15986-7
• Support Opportunities: Scholarships in Brazil - Master
• Start date: February 01, 2017
• End date: January 31, 2019
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Ana Carolina Migliorini Figueira
• Grantee: Edwin Fernando Vásquez Vásquez
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Campinas , SP, Brazil

Abstract

In the absence of their cognate ligands, some nuclear hormone receptors including thyroid hormone receptor (THR) act as transcriptional repressors by recruiting corepressor complexes to target genes. This constitutive repression is crucial in metazoan reproduction, development and homeostasis. However, its specific molecular determinants remain obscure. In addition, mutations in two THR isoforms (THR± and THR²) have been found in the resistance to thyroid hormone syndrome (RTH) and in human renal clear cell carcinomas (RCCCs). The goal of this project is to provide understanding of the mechanistic aspects of the transcriptional repression mediated by wild-type and mutant THRs. Our objective is to obtain more information about the structures of THRs, as isolated ligand binding domain, in complex with corepressors (CoRs), in their physiological and pathological forms using X-ray crystallography and SAXS (Small Angle X-ray Scattering). In addition, we will make use of biophysical methods (fluorescence anisotropy, MicroScale Thermophoresis) to explore the specificity of interaction between the different THRs and CoRs. The understanding the mechanisms of interaction between wild-type or mutant THRs and CoRs at the atomic resolution could serve for the design of compounds that are able to modulate the aberrant interactions and/or abnormal activations involved in different diseases. (AU)

Scientific publications

(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)

HARRUS, DEBORAH; DEMENE, HELENE; VASQUEZ, EDWIN; BOULAHTOUF, ABDELHAY; GERMAIN, PIERRE; FIGUEIRA, ANA CAROLINA; PRIVALSKY, MARTIN L.; BOURGUET, WILLIAM; LE MAIRE, ALBANE. Pathological Interactions Between Mutant Thyroid Hormone Receptors and Corepressors and Their Modulation by a Thyroid Hormone Analogue with Therapeutic Potential. THYROID, v. 28, n. 12, OCT 2018. (16/15986-7)