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Description
Multicellular organisms use a multistep process called signal transduction for cell to cell communication. Messaging cells will secrete soluble, extracellular signals to recipient cells. The extracellular signal will bind to cell surface receptors of the recipient cells that then trigger signaling cascades within the cell, to elicit a physiological response. Our interest is in receptor tyrosine kinases (RTKs) and their role in signal transduction. One protein that associates with activated RTKs is Shc. Shc is a receptor binding protein that also interacts with Grb2, a protein at the initial stage of the Ras-MAP Kinase pathway. We have evidence that Shc has more functions than acting as an adaptor for receptors and Grb2. We have identified another Shc binding protein, Suppressor of T-cell receptor Signaling-1 (STS-1) which has not been previously reported. STS-1 bound to Shc in a phosphorylation dependent manner, leading us to look into this protein and investigate how these proteins are binding. There are four domains within STS-1: the amino terminus contains a ubiquitin-associated (UBA) domain, a 2 histidine phosphoesterease (2HPE) domain, and a Src homology 3 (SH3) domain while a phosphoglycerate mutase homology (PGM) domain resides in the carboxyl terminus. There are previous studies indicating that the PGM domain has phosphatase activity and the crystal structure of this domain has been solved. Our focus is determining how STS-1 recognizes phosphotyrosine residues. Based on the Simple Modular Architecture Research Tool (SMART), there are no phosphotyrosine binding domains (SH2, PTB, C2, or HYB) in STS-1. We hypothesize that there must be a novel phosphotyrosine binding domain within STS-1. Using recombinant STS-1 constructs, we plan on using X-ray crystallography to find out which residues in this domain are associating with the tyrosine phosphorylated peptide substrate by comparing unbound and bound crystal structures.
