Study of Conformational Dynamics and Stability of Metastates for TMEM176 and its Role in Inflasome Activation

• Grant number: 23/01920-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date until: October 01, 2023
• End date until: September 30, 2025
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Ana Lígia Barbour Scott
• Grantee: Simone Queiroz Pantaleão
• Host Institution: Centro de Matemática, Computação e Cognição (CMCC). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil

Abstract

TMEM176 proteins are an ion channel expressed in immune cells and certain types of cancer. The transmembrane proteins TMEM176A and 176B belong to the CD20/Fc-µRI² and membrane-spanning 4A (MS4A) family of proteins. Human TMEM176B (also known as LR8) was first discovered in human lung fibroblasts, and was recently associated in human small cell lung carcinoma . Similar to TMEM176A, the level of human TMEM176B transcripts has been shown to be markedly elevated in transplanted livers that showedrecurrence of HCV infection. In many cancers, differential regulation of the expression of TMEMs has been observed. Recent results from Prof. Marcelo Hill showed that TMEM176B expression is inversely correlated with inflammasome activation in critically ill patients with COVID-19. Furthermore, overexpression of TMEM176B inhibited protein-induced inflammasome activation in human monocytes. In vivo, Tmem176b-/- mice succumb to betacoronavirus MHV-A59 in an inflammasome-dependent manner. A significant number of works in the literature show the importance of ion channels (TMEM)-176A and 176B and that they have an important role in the immune system that needs to be better understood. Although these macromolecules (176A, 176B and 176AB) exert important functions and several cellular processes, structural details as well as the conformational dynamics remain poorly understood. Furthermore, although the number of in vitro works on the functionality of TMEM176 is expressive, in silico studies that explain its conformational dynamics and the stability of its metastases are practically non-existent.The in silico study proposed in this project together with the experimental data described in the literature, especially in collaboration with Dr. Marcelo Hill, can contribute significantly to a better understanding of the molecular mechanisms of (TMEM)-176A and 176B (homodimers) and its heterodimer form.