9B4P

Tetramer Formation of the BCL11A ZF0 Domain

9B4P の概要

• エントリーDOI: 10.2210/pdb9b4p/pdb
• 分子名称: B-cell lymphoma/leukemia 11A, ZINC ION (3 entities in total)
• 機能のキーワード: sickle cell disease, bcl11a, tetramerization, hemoglobin, transcription factor, transcription
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 10
• 化学式量合計: 33062.92

構造登録者

Yin, M.,Tenglin, K.,Orkin, S.H. (登録日: 2024-03-21, 公開日: 2024-12-18)

主引用文献

Zheng, G.,Yin, M.,Mehta, S.,Chu, I.T.,Wang, S.,AlShaye, A.,Drainville, K.,Buyanbat, A.,Bienfait, F.,Tenglin, K.,Zhu, Q.,Orkin, S.H.
A tetramer of BCL11A is required for stable protein production and fetal hemoglobin silencing.
Science, 386:1010-1018, 2024

PubMed Abstract: Down-regulation of BCL11A protein reverses the fetal (HbF, αγ) to adult (HbA, αβ) hemoglobin switch and is exploited in gene-based therapy for hemoglobin disorders. Because of reliance on ex vivo cell manipulation and marrow transplant, such therapies cannot lessen disease burden. To develop new small-molecule approaches, we investigated the state of BCL11A protein in erythroid cells. We report that tetramer formation mediated by a single zinc finger (ZnF0) is required for production of steady-state protein. Beyond its role in protein stability, the tetramer state is necessary for γ-globin gene repression, because an engineered monomer fails to engage a critical co-repressor complex. These aspects of BCL11A protein production identify tetramer formation as a vulnerability for HbF silencing and provide opportunities for drug discovery.

PubMed: 39607926
DOI: 10.1126/science.adp3025

実験手法

X-RAY DIFFRACTION (2.56 Å)