Drosophila Yorkie (Yki) and its vertebrate ortholog, Yes-associated protein (Yap), are transcription co-activator proteins that do not bind DNA directly, but instead utilize interactions with multiple DNA-binding partners to elevate transcription of growth-promoting and anti-apoptosis target genes. Their role as major effectors of cell growth and anti-apoptosis has been linked to tumor formation. Yki/Yap is a downstream regulatory target of the Hippo pathway, a highly conserved signaling pathway which is critical to the precise control of organ size. Activation of hippo signaling leads to phosphorylation of key serine residues, and promote protein-protein interactions that inhibit the transcription co-activator proteins. Hippo signaling also induces degradation of Yap by recruiting the E3 ubiquitin ligase SCFβ-RCP complex. Current research is primarily focused on protein-protein interactions that inhibit Yki by modulating its subcellular localization. We combine NMR solution structure and dynamics with thermodynamics and other biophysical techniques to investigate recognition specificity and how this leads to effective inhibition. The ultimate goal is to use this fundamental knowledge to design small molecules that can act as selective inhibitors and prevent tumorigenesis.
