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

Abstract

TEAD (<i>TEA</i>/ATTS <i>d</i>omain) transcription factors are the most distal effectors of the Hippo pathway. YAP (<i>Y</i>es-<i>a</i>ssociated <i>p</i>rotein) 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 YAP:TEAD interaction is an attractive therapeutic strategy for oncology. Understanding the molecular events that take place at the YAP:TEAD 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 YAP:TEAD interface. Our results provide quantitative understanding of the interactions taking place at the YAP:TEAD interface and give insights into the formation of the YAP:TEAD complex and more particularly on the interaction between TEAD and the Ω-loop found in YAP.