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Analysis of the interaction between the SH2 domains of phospholipase Cg, with the loop containing the activating tyrosine Y783, and the impact on PLCg activation by NGF

Grant number: 22/11236-4
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): November 01, 2022
Effective date (End): October 31, 2023
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Deborah Schechtman
Grantee:Vinícius Pinheiro Biazotti
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:19/06982-6 - Characterization and development of new modulators of the TrkA and PKMzeta pathways in inflammatory and chronic pain, AP.TEM

Abstract

When a tissue injury is produced in the human body, there are several forms of cell signaling of pain. The research interest of our laboratory group is mediated by the dimerization of the TrkA receptor (Tropomyosin kinase A) and a consequent cascade of reactions until neuronal depolarization, through activation of the TRPV1 cation channel.In this inflammatory context, the first step is the secretion of Neural Growth Factor (NGF) by cells in the region of tissue injury. This compound leads to the activation of the TrkA receptor, a protein with high affinity for NGF, which dimerizes activating several signaling pathways. Among them, the phospholipase Cg (PLCg) pathway. This phospholipase, when phosphorylated, cleaves membrane lipids, leading to the activation of a cation channel called TRPV1, carrying the signal to the central nervous system. Studies carried out by our laboratory concluded that the inhibition of the interaction between PLCg and the dimerized receptor TrkA, through the use of a mimetic peptide, derived from the site of interaction of TrkA with PLCg (TAT-pQYP), inhibited the interaction and PLCg activation as well as mechanical nociception in an inflammatory model, demonstrating the importance of PLCg activation for nociception. Therefore, this result highlighted even more the importance of studying the interaction between the Tropomyosin kinase A receptor and PLC. Phospholipase Cg contains two SH2 domains: one N and one C. It is proposed that N-SH2 binds to TrkA, enabling the phosphorylation of Y783 of PLCg, whereas the C-SH2 domain of PLCg then binds to phosphorylated Y783, which causes a conformational change in the lipase, activating it. Thus, in the present project, we aim to study the affinity of the N and C-SH2 domains for a peptide containing the phosphorylated Y783 and if this peptide also inhibits the binding of PLCg to TrkA and/or inhibits a conformational change/activation of PLC , which may inhibit nociception.We therefore aim to develop a more specific inhibition mechanism for PLCg, and highly effective non-opioid analgesics.

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