Sketch of a tandem zinc finger domain in contact with a class II AU-rich element (PDB: 1RGO).
Side chains involved in stacking interactions with nucleic acids (red) are shown in blue.


Regulation of gene expression by changes in mRNA stability is one of the most important control mechanisms of gene expression in the immune system. The decay rate of mRNA is regulated by cis-acting elements in the 3′ untranslated regions of mRNA. The most prominent regulatory elements are the so called AU-rich elements (AREs). AREs recruit various ARE-binding proteins that possess RNA stabilizing or destabilizing functions. One of the key mRNA-destabilizing is tristetraprolin (TTP). TTP deficiency leads to serious inflammation and eventually death in animal models caused most likely by insufficient removal of proinflammatory mRNAs such as TNF-ɑ. The biological function of TTP is still not completely understood due to the lack of animal models with conditional regulation of TTP expression. Further, no structural data about TTP and TTP-target RNA binding are available. These shortcomings preclude a comprehensive understanding of TTP function and the mechanism of TTP-mediated mRNA decay. In the proposed multidisciplinary project, TTP targets will be identified by a number of large scale experimental methods. The sequence of these mRNAs will be investigated for the presence of common sequence and structural elements using bioinformatics and structural biology. Based on these data, prediction tools for TTP targets will be developed and integrated in a searchable TTP target database that will be publically accessible via the internet. In addition, using the prediction tools modifiers (small RNA molecules) of the TTP binding will be designed and subsequently experimentally tested for their potential to modulate TTP function in vivo. The proposed project uses structural biology in combination with bioinformatics and cell based approaches to decipher TTP-mediated mRNA decay and ultimately the TTP function.

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