7X88

Crystal structure of ENL YEATS domain T2 mutant in complex with histone H3 acetylation at K27

7X88 の概要

• エントリーDOI: 10.2210/pdb7x88/pdb
• 分子名称: Protein ENL, Histone H3K27ac(24-27) peptide, CITRIC ACID, ... (4 entities in total)
• 機能のキーワード: yeats domain, complex, histone, transcription, gene regulation
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 19006.77

構造登録者

Li, Y.Y.,Li, H.T. (登録日: 2022-03-11, 公開日: 2023-01-18, 最終更新日: 2024-10-23)

主引用文献

Song, L.,Yao, X.,Li, H.,Peng, B.,Boka, A.P.,Liu, Y.,Chen, G.,Liu, Z.,Mathias, K.M.,Xia, L.,Li, Q.,Mir, M.,Li, Y.,Li, H.,Wan, L.
Hotspot mutations in the structured ENL YEATS domain link aberrant transcriptional condensates and cancer.
Mol.Cell, 82:4080-4098.e12, 2022

PubMed Abstract: Growing evidence suggests prevalence of transcriptional condensates on chromatin, yet their mechanisms of formation and functional significance remain largely unclear. In human cancer, a series of mutations in the histone acetylation reader ENL create gain-of-function mutants with increased transcriptional activation ability. Here, we show that these mutations, clustered in ENL's structured acetyl-reading YEATS domain, trigger aberrant condensates at native genomic targets through multivalent homotypic and heterotypic interactions. Mechanistically, mutation-induced structural changes in the YEATS domain, ENL's two disordered regions of opposing charges, and the incorporation of extrinsic elongation factors are all required for ENL condensate formation. Extensive mutagenesis establishes condensate formation as a driver of oncogenic gene activation. Furthermore, expression of ENL mutants beyond the endogenous level leads to non-functional condensates. Our findings provide new mechanistic and functional insights into cancer-associated condensates and support condensate dysregulation as an oncogenic mechanism.

PubMed: 36272410
DOI: 10.1016/j.molcel.2022.09.034

実験手法

X-RAY DIFFRACTION (2.25 Å)