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We are developing the Drosophila expression system to study both mammalian proteins of interest for medical research, and Drosophila homologues of these proteins, which may serve as useful models for understanding the structure and function of the mammalian counterparts. For high resolution structural analysis, we rely largely on the technique of X-ray crystallography.
The Problem: Human proteins are the ultimate target for most studies that lead to novel therapies, pharmaceuticals or understanding of disease. However, handling human proteins by purification or overexpression can be extremely difficult and normally does not yield sufficient quantities for molecular studies. Traditional Structural Genomics approaches of E. coli expression, when they work, have the advantage of speed, simplicity, and good yields. However, many (most) proteins of interest do not behave well when expressed in bacteria, or may not resemble their naturally-produced counterparts, for example in post-translational processing.
The Approach: Drosophila has been used for over a century as a research tool by geneticists. It has become popular as a model for understanding mammalian pathways, such as signal transduction and developmental pathways. The evolutionary relationship between Drosophila and mammals is close enough for the corresponding molecules responsible for many functions to be closely related structurally between the species. Furthermore, the protein synthesis and folding environments are more similar between mammals and Drosophila, as compared to bacteria.
Thus, we hypothesize that:
- Many mammalian proteins will be more amenable to overexpression in Drosophila cells than bacteria;
- For many mammalian functions/molecules of interest, there are structurally-related Drosophila proteins that can be used as experimental models. Many of these can be homologously overexpressed in the Drosophila cell expression system.