The long-term goal of the proposed study is to understand how signal is transduced across the membrane of a living cell. Neuropeptides/proteins bind to their receptors to exert different biological functions, providing a good system to study the mechanism of signal transduction. The receptors are often transmembrane proteins with a single transmembrane helix. A common theme begins to emerge among those receptors involved in signal transduction. It is apparent that the binding of a ligand to the extracellular domain of its receptor(s) is the first step of signaling. However, structural understanding of how this binding is then transduced to the downstream components of signaling pathway is much needed. One school of thought is that the ligand binding to a receptor induces an oligomerization (homo- or hetero-) of responsive receptors. This notion forms the underlying basis for the signaling mechanism of growth factor as well as growth factor-like cytokines such as tumor necrosis factor. It is commonly called """"""""receptor clustering"""""""" and has been proposed for many known cytokine receptors. Crystal structures of human growth factor/receptor complex and tumor necrosis factor/receptor complex support the idea of """"""""receptor clustering"""""""". Crystal structure of MHC II also suggests a possibility that the peptide/MHC II complex induces dimerization of receptors. In our proposed study, we plan to focus on activin and activin/receptor complex. Activin interacts with two types of receptors in a unique manner. Unlike most transmembrane receptors known to be tyrosine phosphorylating, this group of receptors is serine/threonine kinase active. In addition, only type II receptor is known to bind to activin although the binding of type I receptor with the complex of type II receptor with the ligand is required. Both types of receptors have serine kinase activity in their cytoplasmic domains, and the activity of both are required for signaling. Recombinant forms of activin and the ligand-binding domain of activin receptors are now available in quantity. Chemical and biophysical characterization of activin and its receptor may provide a clue to a better understanding of the nature of interaction. Crystal structures of activin and its complex with the receptor will be studied by X-ray crystallographic methods. The three-dimensional structures of activin and the complex of activin with its receptor would provide a good model, defining he binding interface at atomic resolution. Conformational changes of type II receptor responding to activin binding may trigger the further cascade of signaling pathway, providing an important clue is understanding the structural basis of signaling mechanism across the membrane. Atomic models defining the binding specificity of neuropeptides such as activin and gonadotropin-releasing hormone would also facilitate the design of effective and long-lasting peptidomimetic drugs that would be useful in modulating various hormone-related diseases.
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