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 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.DOI: http://dx.doi.org/10.7554/eLife.25068.001

A new perspective on the evolution of the interaction between the Vg/VGLL1-3 proteins and the TEAD transcription factors

“…This mutation in TEAD1, Tyr421His TEAD1 , which is at the root of Sveinsson's chorioretinal atrophy (Fossdal, Jonasson et al, 2004), has a major negative impact on the YAP:TEAD complex (Bokhovchuk, Mesrouze et al, 2019). Asp246Ala Sd and Tyr435His Sd were purified, and their CD spectrum shows that the mutations do not affect the structure of Sd ( Fig S4B) as previously observed with the corresponding TEAD4 mutations (Bokhovchuk et al, 2019, Mesrouze et al, 2017a. The affinity of Vg 263-382 and of Yki 30-146 for Asp276Ala Sd is reduced by 1.58 and 3.6 kcal/mol, respectively (Table 2) and the Tyr435His Sd mutation lowers the binding of Vg 263-382 and of Yki 30-146 by 2.44 and 4.11 kcal/mol, respectively (Table 2).…”

“…This suggests that the presence of a larger aromatic residue at this position might be sufficient to stabilize and shield the hydrophobic core of the bound Ω-loop from solvent. The key salt bridge between Arg89 YAP and Asp272 TEAD4 found in the YAP:TEAD complex (Mesrouze, Bokhovchuk et al, 2017a) is also observed between Arg327 Vg and Asp276 Sd in the Vg:Sd complex ( Fig 2F). Finally, Ser332 Vg is within hydrogen bond distance of Glu267 Sd :Tyr435 Sd , as is the case for Ser94 YAP and Glu263 TEAD4 :Tyr409 TEAD4 in the YAP:TEAD complex ( Fig 2F).…”

“…The β-strand:α-helix region of YAP (YAP 44-74 ) has a low affinity for TEAD (Mesrouze et al, 2014) while its Ω-loop (YAP 85-99 ), binds more tightly to it (Hau et al, 2013, Zhang, Lin et al, 2014. Consequently, mutations in the Ω-loop binding pocket of TEAD are more destabilizing than mutations in the β-strand:αhelix binding pocket (Li et al, 2010, Mesrouze et al, 2017a. Since the β-strand:α-helix region of Vg (Vg 288-311 ) has a high affinity for wt Sd (Table1), we hypothesized that the Vg:Sd complex might be more permissive to mutations in the Ω-loop binding pocket of Sd than the Yki:Sd complex, which should behave like the YAP:TEAD complex.…”

Hippo‐Yap/Taz signaling: Complex network interactions and impact in epithelial cell behavior

“…TEADs are potent Yap binding partners interacting through an α‐helix and a Ω‐loop in Yap. Point mutations in these regions abrogate Yap‐TEAD interactions and inhibit Yap‐induced gene expression (Goulev et al, ; Mesrouze et al, ; Oh et al, ; Vassilev, Kaneko, Shu, Zhao, & Depamphilis, ; Wu, Liu, Zheng, Dong, & Pan, ; L. Zhang et al, ; B. Zhao, Ye, et al, ). ChIP‐seq studies on anti‐TEAD siRNA‐treated samples show that TEAD knockdown obliterates Yap ChIP‐seq peaks (Stein et al, ).…”

“…TEADs are potent Yap binding partners interacting through an α-helix and a Ω-loop in Yap. Point mutations in these regions abrogate Yap-TEAD interactions and inhibit Yap-induced gene expression (Goulev et al, 2008;Mesrouze et al, 2017;Oh et al, 2013;Vassilev, Kaneko, Shu, Zhao, & Depamphilis, 2001;Wu, Liu, Zheng, Dong, & Pan, 2008;B. Zhao, Ye, et al, 2008).…”