Structural Analysis and Anchoring Mechanism of the Transmembrane emp24 domain-containing Proteins

• Grant number: 25/02603-1
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: May 01, 2025
• End date: April 30, 2029
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Antonio José da Costa Filho
• Grantee: Gabriel Machado de Oliveira
• Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 23/04532-9 - The exquisite biophysics of the unconventional protein secretion: old and new looks to old and new problems, AP.TEM

Abstract

This project aims to conduct a detailed structural analysis and investigate the anchoring mechanism of Transmembrane emp24 domain-containing (TMED) proteins, with a focus on human TMED10. These transmembrane proteins play a crucial role in the classical secretion pathway, regulating molecular trafficking between the endoplasmic reticulum (ER) and the Golgi complex. Recently, TMED10 has been identified as a vesicular translocation channel involved in the secretion of signal peptide-lacking proteins, a process termed TMED10-channeled UPS (THU). Additionally, the interaction between TMED1 and the ST2 protein, mediated by the TMED1 GOLD domain and the ST2 TIR domain, suggests a significant role of these proteins in immune signaling and inflammatory response regulation. This project proposes the structural and functional characterization of these interactions using spectroscopic approaches, size-exclusion chromatography coupled with multi-angle light scattering (SEC-MALS), and cryo-electron microscopy. The study aims to enhance the understanding of TMEDs' role in intracellular trafficking and their physiological implications, potentially providing insights for future therapeutic interventions in diseases associated with these proteins. (AU)