Structural basis for the role of K-homology Splicing Regulator Protein in mRNA turnover. (360G-Wellcome-082088_Z_07_Z)

mRNA stability is an important parameter in determining the level of gene expression and can be selectively regulated. Adenine uracil-rich elements (AREs)-mediated mRNA decay (AMD) modulates the stability of many mRNAs that encode transcription factors and other regulatory proteins. In AMD, ARE-binding proteins (ABPs) recruit the exosome to long AREs embedded in the 3 untranslated region (3 UTR) of selected mRNAs. However the specificity of ABP-ARE interactions (and therefore of exosome recruit ment) is poorly understood at the molecular level. It seems likely that the recognition of the long ARE sequences by ABPs is based on multiple protein-RNA interactions and that RNA structural elements play a role. This hypothesis is supported by functional studies on several ABPs, but also by our preliminary biophysical results with the functionally well-characterised K-homology Splicing Regulator Protein (KSRP). These results also indicate that interactions between the domains of the protein pl ay a role in recognition. We want to solve the structure of the RNA binding region of KSRP alone and in complex with both single stranded and partially structured RNA targets. The fundamental question we wish to answer is how ARE recognition is linked to the RNA structure and to the interactions existing between protein domains.