The objective of the proposed studies is to investigate the molecular mechanisms underlying the specific regulatory and targeting interactions of the Wnt signaling pathways by using structural and biophysical methods. Wnt signaling plays an important role in embryonic development and in the regulation of cell growth. Inappropriate activation of Wnt signaling has been implicated in cancers and other human diseases. Dishevelled (Dvl), an important component of the Wnt signaling pathways, relays signals from the membrane-bound Wnt receptor Frizzled (Fz) to downstream partners. Different Wnt signaling pathways diverge at the level of Dvl. However, the mechanism by which Dvl transduces the Wnt signals is unclear, as are the molecular events that regulate pathway specification at the level of Dvl. The proposed structural and biophysical analyses will address these questions by elucidating the fundamental chemical nature of the interactions between Dvl and its binding partners. Dvl is hypothesized to undergo conformational changes upon receiving Wnt signals. Protein NMR spectroscopy will be used to investigate these conformational changes and the mechanism of their regulation by molecular interactions of Dvl and its binding molecules.
The Specific Aims are to 1) Determine the binding specificities between the PDZ domains of Dvl proteins and the C-termini of Fz receptors by protein NMR spectroscopy and other physical biochemistry methods;2) Identify components of the regulatory network that mediates the function of the Dvl proteins;and 3) Ascertain whether Dvl undergoes a conformational change in the transduction of Wnt signaling. The knowledge gained from these investigations will not only help to explain the fundamental chemical nature of the complex molecular interplay at the level of Dvl in Wnt signaling but will also shed light on the maintenance of intracellular signal specificity and the nature of global signaling control. These findings may also be useful in formulating rational approaches to the development of novel pharmaceutical agents that can interfere with specific Wnt signaling events that contribute to human diseases.
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