研究人员表示，BCL11A蛋白的下调逆转了胎儿血红蛋白（HbF，α2γ2）向成人血红蛋白（HbA，α2β2）的转换，并在基因疗法中被用于治疗血红蛋白疾病。由于依赖于体外细胞操作和骨髓移植，这种疗法无法减轻疾病负担。
为了开发新的小分子方法，研究人员探究了红细胞中BCL11A蛋白的状态。研究人员报告称，由单一锌指（ZnF0）介导的四聚体形成对于稳定蛋白质的生产是必需的。
除了在蛋白质稳定性中的作用外，四聚体状态对于γ-珠蛋白基因的抑制也是必要的，因为工程化的单体无法与关键的共抑制复合物结合。BCL11A蛋白生产的这些特点表明，四聚体形成是HbF沉默的一个脆弱点，并为药物发现提供了机会。
附：英文原文
Title: A tetramer of BCL11A is required for stable protein production and fetal hemoglobin silencing
Author: Ge Zheng, Maolu Yin, Stuti Mehta, I-Te Chu, Stacy Wang, Alia AlShaye, Kirstin Drainville, Altantsetseg Buyanbat, Frédérique Bienfait, Karin Tenglin, Qian Zhu, Stuart H. Orkin
Issue&Volume: 2024-11-29
Abstract: Down-regulation of BCL11A protein reverses the fetal (HbF, α2γ2) to adult (HbA, α2β2) 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.
DOI: adp3025
Source: https://www.science.org/doi/10.1126/science.adp3025