Systematic profiling and identification of the peptide‐mediated interactions between human Yes‐associated protein and its partners in esophageal cancer

Abstract

Human Yes-associated protein (YAP) is involved in the Hippo signaling pathway and serves as a coactivator to modulate gene expression, which contains a transactivation domain (TD) responsible for binding to the downstream TEA domain family (TEAD) of transcription factors and two WW1/2 domains that recognize the proline-rich motifs (PRMs) present in a variety of upstream protein partners through peptidemediated interactions (PMIs). The downstream YAP TD-TEAD interactions are closely associated with gastric cancer, and a number of therapeutic agents have been developed to target the interactions. In contrast, the upstream YAP WW1/2-partner interactions are thought to be involved in esophageal cancer but still remain largely unexplored. Here, we attempted to elucidate the complicated PMIs between the YAP WW1/2 domains and various PRMs of YAP-interacting proteins. A total of 106 peptide segments carrying the class I WW-binding motif [P/L]Px[Y/P] were

Thermostable WW-Domain Scaffold to Design Functional β-Sheet Miniproteins

“…To test this hypothesis, we aimed to engineer the molecular recognition of the binding motifs of the three WW-domain groups on WW-HS-2. WW domains of Group I bind proline-rich motifs of the type PPxY (x: any amino acid), ligands of Group II/III show a characteristic PPLP/PPRP motif, and those of Group IV bind phosphorylated ligands of the type pS/pTP . Using computer-simulated alanine scanning on existing NMR spectroscopic and X-ray crystal structures solved for WW domains of the respective groups, we were able to identify residues at the ligand-binding sites that are important for the function of the respective WW domain (Table S4).…”

SRY-Box transcription factor 9 triggers YAP nuclear entry via direct interaction in tumors

“…The formation of YAP-partner complexes under certain pathological conditions makes YAP an ideal drug target. [44][45][46] Dissociation of coactive YAP partners has been shown to have potential therapeutic effects in the treatment of cancers. For instance, verteporfin (a porphyrin compound) blocked the YAP-TEAD interaction and suppressed ovarian cancer growth in mice.…”