Double the Double: Revisiting BCL11B's Multimerization.

IF 3.2 4区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Proteins-Structure Function and Bioinformatics Pub Date : 2025-07-01 Epub Date: 2025-02-20 DOI:10.1002/prot.26811

Anne Susemihl, Norman Geist, Piotr Grabarczyk, Christian A Schmidt, Mihaela Delcea, Lukas Schulig

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引用次数: 0

Abstract

The transcription factor B Cell Lymphoma/Leukemia 11B (BCL11B) exerts a bi-directional function in cancer, with its role as an emerging therapeutic target in cancer treatment being particularly intriguing. BCL11B knockouts in cultured T cells revealed the acquisition of properties characteristic of natural killer cells, hinting at its importance in innate versus adaptive immune regulation. Our previous studies using Förster Resonance Energy Transfer-assisted Fluorescence-Activated Cell Sorting and Hybrid Solvent Replica-Exchange Simulations indicated that BCL11B forms dimers, with this being a prerequisite for its activity. However, size exclusion chromatography and crosslinking experiments have challenged this view, suggesting that BCL11B forms tetramers instead. An atypical CCHC zinc finger motif within the N-terminal region of the protein mediates multimerization and a novel 3D structure is presented based on extensive replica-exchange simulations in strong agreement with experimental data. The physiological relevance of multimer formation of this zinc finger protein has been demonstrated previously. Therefore, understanding the nature of BCL11B's multimerization could potentially enhance our ability to target this protein effectively, hopefully paving the way for novel BCL11B-targeted therapies.

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双重双重：重新审视BCL11B的多用途化。

转录因子B细胞淋巴瘤/白血病11B （BCL11B）在癌症中发挥双向作用，其作为一个新兴的治疗靶点在癌症治疗中的作用尤其引人注目。培养T细胞中的BCL11B敲除揭示了自然杀伤细胞特性的获得，暗示其在先天与适应性免疫调节中的重要性。我们之前使用Förster共振能量转移辅助荧光活化细胞分选和混合溶剂复制交换模拟的研究表明，BCL11B形成二聚体，这是其活性的先决条件。然而，尺寸排除色谱和交联实验挑战了这一观点，表明BCL11B形成四聚体。在蛋白质的n端区域，一个非典型的CCHC锌指基序介导多聚，并且基于广泛的复制交换模拟，提出了一种新的3D结构，与实验数据非常一致。这种锌指蛋白的多重形成的生理相关性已经被证明了。因此，了解BCL11B多聚化的本质可能会提高我们有效靶向这种蛋白质的能力，有望为新的BCL11B靶向治疗铺平道路。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Proteins-Structure Function and Bioinformatics 生物-生化与分子生物学

CiteScore

5.90

自引率

3.40%

发文量

172

审稿时长

3 months

期刊介绍： PROTEINS : Structure, Function, and Bioinformatics publishes original reports of significant experimental and analytic research in all areas of protein research: structure, function, computation, genetics, and design. The journal encourages reports that present new experimental or computational approaches for interpreting and understanding data from biophysical chemistry, structural studies of proteins and macromolecular assemblies, alterations of protein structure and function engineered through techniques of molecular biology and genetics, functional analyses under physiologic conditions, as well as the interactions of proteins with receptors, nucleic acids, or other specific ligands or substrates. Research in protein and peptide biochemistry directed toward synthesizing or characterizing molecules that simulate aspects of the activity of proteins, or that act as inhibitors of protein function, is also within the scope of PROTEINS. In addition to full-length reports, short communications (usually not more than 4 printed pages) and prediction reports are welcome. Reviews are typically by invitation; authors are encouraged to submit proposed topics for consideration.