G protein-coupled receptors (GPCRs), the largest family of membrane proteins on the cell surface, play essential roles in signal transduction in all eukaryotic organisms. These proteins are responsible for sensing and detecting a wide range of extracellular stimuli and translating them to intracellular responses. This signaling requires a tight control for receptor activation without which abnormal signal leads to diseases. In fact, malfunctions of these receptors are associated with numerous pathological conditions and currently an estimated 40-50% of therapeutic drugs are designed to target these receptors suggesting that further increases in understanding of GPCRs and the signaling pathways they initiate will lead to new and more specific drug targets. We have used Saccharomyces cerevisiae GPCR Ste2p as a model system to understand structure-function relationships of these receptors. In this study, the role of the extracellular N-terminus has been examined using various biophysical methods with the anticipation to uncover its role in receptor function. It was found that some residues in the extracellular N-terminus were not accessible to a sulfhydryl reagent and that the alternating pattern of accessibility is consistent with the structure of a beta strand. This beta strand was found to be involved in dimer formation. Moreover, a conserved tyrosine residue in the middle of the beta strand was found to interact with two residues in the extracellular loop 1. It was also found that the N-terminus is involved in negative regulation and important for cell surface expression
