Characterization of GRB2 and SOS1 binding downstream of TCR activation

Despite their essential role in protection, T cells can be dangerous if unregulated. Dysfunctional T cell activity has been implicated in numerous diseases, including the failure of organ transplants, allergic reactions, multiple sclerosis, and coronary artery disease. Signal transduction pathways activated by the T cell receptor (TCR) are good targets for the development of therapies. However, we must first better understand the mechanisms of intracellular signaling that occur when a T cell is activated. This thesis focuses on the scaffold protein LAT and its role in T cell activation. The localization of signaling proteins into LAT-nucleated complexes and subsequent aggregation of these complexes into microclusters is vital for the activation of intracellular signaling pathways, and the effector functions of T cells. Following TCR stimulation, LAT is phosphorylated and binds SH2 domain containing molecules, such as the adaptor protein Grb2. One LAT molecule is capable of binding up to three Grb2 molecules at one time. Grb2 also binds to the proline rich regions of several proteins, including SOS1. Recent studies indicate that at physiological ratios of Grb2 and SOS1, two Grb2 molecules bind to one SOS1 proline rich region, and this 2:1 stoichiometry is essential for LAT oligomerization and cluster formation. The interaction of Grb2 and SOS1 is considered to be a model SH3 domain interaction, and has biased our understanding of these relationships for decades. Many studies have focused on the association between the Grb2