Binding specificity evaluation of SH2 domains present in PLC gamma by peptides derived of tyrosine kinases

• Grant number: 21/12989-3
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: January 01, 2022
• End date: June 30, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Deborah Schechtman
• Grantee: Noemi Jacó de Souza
• 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 observing an inflammatory context generated by a tissue injury, it is found pro-inflammatory factors, amongst them the nerve growth factor (NGF). The secreted NGF binds to its high-affinity receptor, named TrkA, a tyrosine kinase coupled receptor, leading to the kinase activation and a signaling cascade. Several cellular phenomena occur upon this cascade, such as neuronal differentiation, maturation, survival, and synaptic plasticity, the latter being mediated by activation through phosphorylation of phospholipase C gamma (PLC gamma). Thus, it is important to notice that the activation of PLC gamma leads to the opening of a cations channel, TRPV1, conducting to neuronal depolarization. In vivo studies conducted by our group indicated that the inhibition of PLCgamma interaction with TrkA by using a C-terminus receptor region mimetic peptide (peptide 1) led to analgesia. Considering that, it is important to get more information regarding the specificity of such interaction through a structural basis. Taking into account that PLC gamma presents two SH2 domains that interact with phosphorylated tyrosines, and that peptide 1 blocks interaction of PLCgamma and TrkA, our objective is to know the specificity of this peptide interacting with each SH2 domain, and also derivate peptides from interaction sites of Trks A and B with PLC gamma. Using methodologies of interaction protein-peptide, these studies will be conducted to obtain information regarding the selectivity of SH2 PLC gamma domains on the interaction with Trks. (AU)