Tristetraprolin or TTP is a basic proline-rich protein that is the prototype of a class of Cys3His zinc finger proteins. Mice deficient in TTP develop a complex syndrome consisting of arthritis, wasting, dermatitis, and early death. Recent work has identified TNF alpha excess as the cause of most, if not all, aspects of the syndrome, and recently TTP has been shown to bind to the AU-rich element in the 3 untranslated region of TNF alpha mRNA initiating its destabilization. Other Cys3His zinc finger proteins appear to be involved in RNA metabolism or are part of RNA viruses, suggesting that this class of zinc fingers may interact with RNA. The goal of this project, a collaboration with Dr. Perry Blackshears group in the Laboratory of Signal Transduction, is to determine the crystal structure of TTP alone or in complex with its binding partner. This structure will shed light on the mechanism by which TTP regulates TNF alpha production and provide a basis for understanding the function of other members of the Cys3His zinc finger family and their mode of interaction with specific binding partners. Experimental evidence suggests that TNF alpha- blocking agents may be useful for the treatment and/or prevention of rheumatoid arthritis, inflammatory bowel disease, brain injury, and heart disease. Therefore, TTP or mimics of its effects on TNF alpha production may serve as potential therapeutic agents. A crystal structure of TTP will provide insight into the mechanism by which TTP regulates TNF alpha production and an atomic model to guide the design of small molecule compounds that can mimic its activity. - TTP, TNF alpha, crystallography, zinc finger
