8WRG

Solution structure of the TAD domain (450-504) of human transcriptional coactivator YAP1

Summary for 8WRG

• Entry DOI: 10.2210/pdb8wrg/pdb
• Descriptor: Transcriptional coactivator YAP1 (1 entity in total)
• Functional Keywords: transcriptional coactivator, transcription factor complex, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 7048.79

Authors

Zhang, H.,Li, Y. (deposition date: 2023-10-14, release date: 2024-10-16, Last modification date: 2025-05-28)

Primary citation

Yu, M.,Wang, J.,Zhang, X.,Zhang, H.,Li, C.,Li, J.,Lin, J.,Zheng, J.,Huang, L.,Li, Y.,Sun, S.
The mechanism of YAP/TAZ transactivation and dual targeting for cancer therapy.
Nat Commun, 16:3855-3855, 2025

PubMed Abstract: Transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) play key roles in cancers through transcriptional outputs. However, their transactivation mechanisms remain unclear, and effective targeting strategies are lacking. Here, we show that YAP/TAZ possess a hydrophobic transactivation domain (TAD). TAD knockout prevents tumor establishment due to growth defects and enhances immune attack. Mechanistically, TADs facilitate preinitiation complex (PIC) assembly by recruiting the TATA-binding protein-associated factor 4 (TAF4)-dependent TFIID complex and enhance RNA polymerase II (Pol II) elongation through mediator complex subunit 15 (MED15)-dependent mediator recruitment for the expressions of oncogenic/immune-suppressive programs. The synthesized peptide TJ-M11 selectively disrupts TAD interactions with MED15 and TAF4, suppressing tumor growth and sensitizing tumors to immunotherapy. Our findings demonstrate that YAP/TAZ TADs exhibit dual functions in PIC assembly and Pol II elongation via hydrophobic interactions, which represent actionable targets for cancer therapy and combination immunotherapy.

PubMed: 40274828
DOI: 10.1038/s41467-025-59309-w

Experimental method

SOLUTION NMR