7XEZ

NMR solution structures of p300 TAZ2 domain in complex with BRD4-NUT F1c domain binding motif #2

7XEZ の概要

• エントリーDOI: 10.2210/pdb7xez/pdb
• 分子名称: Histone acetyltransferase p300,NUT family member 1, ZINC ION (2 entities in total)
• 機能のキーワード: brd4-nut fusion protein, cbp/p300, taz2 domain, f1c domain, nut carcinoma, peptide binding protein, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 17570.22

構造登録者

Yu, D.,Zeng, L.,Zhou, M.-M. (登録日: 2022-03-31, 公開日: 2023-04-12, 最終更新日: 2024-10-30)

主引用文献

Yu, D.,Liang, Y.,Kim, C.,Jaganathan, A.,Ji, D.,Han, X.,Yang, X.,Jia, Y.,Gu, R.,Wang, C.,Zhang, Q.,Cheung, K.L.,Zhou, M.M.,Zeng, L.
Structural mechanism of BRD4-NUT and p300 bipartite interaction in propagating aberrant gene transcription in chromatin in NUT carcinoma.
Nat Commun, 14:378-378, 2023

PubMed Abstract: BRD4-NUT, a driver fusion mutant in rare and highly aggressive NUT carcinoma, acts in aberrant transcription of anti-differentiation genes by recruiting histone acetyltransferase (HAT) p300 and promoting p300-driven histone hyperacetylation and nuclear condensation in chromatin. However, the molecular basis of how BRD4-NUT recruits and activates p300 remains elusive. Here, we report that BRD4-NUT contains two transactivation domains (TADs) in NUT that bind to the TAZ2 domain in p300. Our NMR structures reveal that NUT TADs adopt amphipathic helices when bound to the four-helical bundle TAZ2 domain. The NUT protein forms liquid-like droplets in-vitro that are enhanced by TAZ2 binding in 1:2 stoichiometry. The TAD/TAZ2 bipartite binding in BRD4-NUT/p300 triggers allosteric activation of p300 and acetylation-driven liquid-like condensation on chromatin that comprise histone H3 lysine 27 and 18 acetylation and transcription proteins BRD4L/S, CDK9, MED1, and RNA polymerase II. The BRD4-NUT/p300 chromatin condensation is key for activating transcription of pro-proliferation genes such as ALX1, resulting ALX1/Snail signaling and epithelial-to-mesenchymal transition. Our study provides a previously underappreciated structural mechanism illuminating BRD4-NUT's bipartite p300 recruitment and activation in NUT carcinoma that nucleates a feed-forward loop for propagating histone hyperacetylation and chromatin condensation to sustain aberrant anti-differentiation gene transcription and perpetual tumor cell growth.

PubMed: 36690674
DOI: 10.1038/s41467-023-36063-5

実験手法

SOLUTION NMR