Understanding the Role of Juxtamembrane Domain In Regulating VEGFR Activation: A Computational and Experimental Approach

Das, Diptatanu (2022) Understanding the Role of Juxtamembrane Domain In Regulating VEGFR Activation: A Computational and Experimental Approach. Masters thesis, Indian Institute of Science Education and Research Kolkata.

Text (MS dissertation of Diptatanu Das (17MS004)) 17MS004_Thesis_file.pdf - Submitted Version Restricted to Repository staff only Download (8MB)

Abstract

When blood and lymphatic vessels form and get repaired, the signaling pathway controlling the growth and migration of the vascular endothelial cells becomes very important. They are triggered by vascular endothelial growth factors (VEGFs) when these ligands bind to vascular endothelial growth factor receptors (VEGFRs). VEGFRs are the starting point of the downstream signaling cascade that determines the fate of these endothelial cells. Therefore, understanding VEGFR signaling is physiologically very important in the health and disease of higher organisms. There are five mammalian ligands that trigger the three forms of VEGFR in humans. These receptors have architectural similarities with the platelet-derived growth factor receptor (PDGFR) subfamily of the receptor tyrosine kinases (RTKs), with the extracellular immunoglobulin (Ig)-like domain, transmembrane helix and the cytoplasmic region comprised of juxtamembrane domain, kinase domain and C-terminal tail. VEGFR1 and VEGFR2 share high structural and biochemical similarities in all these domains, but interestingly, VEGFR1 shows a very poor kinase activity in contrast to VEGFR2. Why such is the case is the focus of my study here. Previous reports have suggested the probable role of the juxtamembrane domain in stabilizing the autoinhibitory conformation of receptor tyrosine kinases of a related sub-family. However, the mechanism was not conclusively characterized biochemically in case of VEGFR1. In this study, we have used computational and experimental techniques to understand the difference in interactions at the interface of the juxtamembrane domain and the kinase domain between VEGFR1 and VEGFR2 to explain why VEGFR1 has a poor kinase activity in comparison with VEGFR2.

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