Dissection of the interaction between the intrinsically disordered YAP protein and the transcription factor TEAD.

ABSTRACT

TEAD (TEA/ATTS domain) transcription factors are the most distal effectors of the Hippo pathway. YAP (Yes-associated protein) is a coactivator protein which, upon binding to TEAD proteins, stimulates their transcriptional activity. Since the Hippo pathway is deregulated in various cancers, designing inhibitors of the YAPTEAD interaction is an attractive therapeutic strategy for oncology. Understanding the molecular events that take place at the YAPTEAD interface is therefore important not only to devise drug discovery approaches, but also to gain knowledge on TEAD regulation. In this report, combining single site-directed mutagenesis and double mutant analyses, we conduct a detailed analysis on the role of several residues located at the YAPTEAD interface. Our results provide quantitative understanding of the interactions taking place at the YAPTEAD interface and give insights into the formation of the YAPTEAD complex and more particularly on the interaction between TEAD and the Ω-loop found in YAP.