Study of Binding of ZAP-70 Tandem SH2 Domain with ITAM in the Presence of Potassium Ions

G, Vineeth (2021) Study of Binding of ZAP-70 Tandem SH2 Domain with ITAM in the Presence of Potassium Ions. Masters thesis, Indian Institute of Science Education and Research Kolkata.

Text (MS Dissertation of Vineeth G (16MS200)) 16MS200_Thesis_file.pdf - Submitted Version Restricted to Repository staff only Download (1MB)

Abstract

T cell activation is a significant event in the host-pathogen response initiated by the binding between T Cell Receptor (TCR) and the MHC-bound protein/antigen present in the Antigen Presenting Cells. The T cell signaling starts with the recruitment of the Zeta-chain-associated protein kinase 70 (ZAP-70) to the TCR complex, thereby initiating the downstream signaling cascade. ZAP70 is a non-receptor tyrosine kinase belonging to the Syk family of kinases. The structure of ZAP70 consists of an N-terminal regulatory module made up of two tandem Src homology (t-SH2) domains and a C-terminal catalytic module consisting of the Kinase domain, linked by flexible linkers called Interdomains ZAP70 is recruited to the Immuno Tyrosine based Activation Motif (ITAM) present on the CD3 chain of the TCR complex and after that acts as one of the central signaling molecules required for the Tcell activation and downstream responses. One of the ways by which ZAP 70 might be regulated is by the efflux of potassium ions. Potassium has a significant role in maintaining the cell volume, membrane polarity controlling secondary messengers. This work addresses how the ZAP70 tSH2 domains to ITAM and subsequent activation of ZAP 70 at elevated potassium levels. We are interacting with the behaviors of ZAP70 tSH2 via the help of spectroscopy and biochemical studies. Even though potassium is present in high concentration in the cell cytoplasm, an increase in this concentration due to various conditions or infections can lead to silencing of T cell activation and subsequent anergy. These studies can give an insight into how the t cell signaling is being silenced in the high potassium microenvironment, which is a characteristic of tumor cells, and how the cytoplasmic potassium levels may affect autoimmune diseases.

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