Structural and functional analysis of the YAP-binding domain of human TEAD2

Abstract

The Hippo pathway controls organ size and suppresses tumorigenesis in metazoans by blocking cell proliferation and promoting apoptosis. The TEAD1-4 proteins (which contain a DNA-binding domain but lack an activation domain) interact with YAP (which lacks a DNA-binding domain but contains an activation domain) to form functional heterodimeric transcription factors that activate proliferative and prosurvival gene expression programs. The Hippo pathway inhibits the YAP-TEAD hybrid transcription factors by phosphorylating and promoting cytoplasmic retention of YAP. Here we report the crystal structure of the YAP-binding domain (YBD) of human TEAD2. TEAD2 YBD adopts an immunoglobulin-like β-sandwich fold with two extra helix-turn-helix inserts. NMR studies reveal that the TEAD-binding domain of YAP is natively unfolded and that TEAD binding causes localized conformational changes in YAP. In vitro binding and in vivo functional assays define an extensive conserved surface of TEAD2 YBD as the YAP-binding site. Therefore, our studies suggest that a short segment of YAP adopts an extended conformation and forms extensive contacts with a rigid surface of TEAD. Targeting a surface-exposed pocket of TEAD might be an effective strategy to disrupt the YAP-TEAD interaction and to reduce the oncogenic potential of YAP.Hippo pathway | oncogene | crystallography

The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene

“…Our study highlights the potential for YAP as a therapeutic target in ovarian cancer, particularly as reducing YAP levels can partially revert tumorigenic properties of ovarian cancer cell lines such as anchorageindependent growth, resistance to chemotherapeutic drugs, and cell migration and invasion. The TEAD1-4 transcription factors are major effectors of YAP, and the structure of YAP in complex with different TEAD family members was recently reported Li et al, 2010;Tian et al, 2010). Small molecules that inhibit the YAP/ TEAD interaction might thus prove beneficial for treatment of cancers with enhanced YAP activity, such as ovarian clear cell cancer.…”

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…Disruption of YAP-TEAD interaction abolishes YAP-dependent gene transcription and largely diminishes YAP-induced cell proliferation, oncogenic transformation, and epithelial-to-mesenchymal transition (EMT) . The crystal structure of YAP-TEAD complexes reveals that the N-terminal domain of YAP wraps around the globular structure formed by the C-terminal domain of TEAD (Chen et al, 2010b;Tian et al, 2010). Particularly, a short peptide of YAP from residues 86 to 100 plays the most important role in YAP-TEAD interaction by fitting side chains into a deep pocket formed by TEAD.…”

Hippo signaling at a glance

“…The major target transcription factors of YAP, TAZ and Yki are the four proteins of the TEA-domain-containing (TEAD) family (TEAD1-TEAD4), which correspond to a single homologue in Drosophila, Scalloped (Sd) (Goulev et al, 2008;Wu et al, 2008;Zhang, H. et al, 2009;Zhang et al, 2008;Zhao et al, 2008). Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4 Li et al, 2010;Tian et al, 2010). YAP also binds to other transcription regulators, such as Runt-related transcription factor (RUNX), the cytoplasmic domain of ErbB4 and p73, but none of these interactions has been shown so far to mediate the function of YAP in organ size control and tumorigenesis (Komuro et al, 2003;Omerovic et al, 2004;Strano et al, 2001;Yagi et al, 1999).…”