Sołtys Katarzyna, Skowronek Krzysztof, Bystranowska Dominika, Wycisk Krzysztof, Ożyhar Andrzej
Department of Biochemistry, Molecular Biology and Biotechnology, Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, Wrocław, 50-370, Poland.
International Institute of Molecular and Cell Biology, 4 Ks. Trojdena Street, Warsaw, 02-109, Poland.
Cell Commun Signal. 2025 May 26;23(1):243. doi: 10.1186/s12964-025-02247-3.
The human retinoid X receptor γ (hRXRγ) is one of three characterized RXR subtypes, transcription factors belonging to the nuclear receptor superfamily. All RXR subtypes share nearly identical structural elements, including a conserved DNA-binding domain, a D region, a ligand-binding domain, and an F region. However, each subtype possesses a unique N-terminal AB region, which modulates the transcriptional activation of target genes in a cell- and promoter-dependent manner through its ligand-independent activation function involved in protein-protein interactions. Despite the functional significance of the AB region, its structural contributions, particularly in the context of the full-length receptor, remain largely unexplored. Here, we uncover the role of the AB region of hRXRγ in modulating the molecular properties of the receptor. A comparative analysis of the full-length receptor (hRXRγ) and a deletion mutant lacking the AB region (ΔABhRXRγ) highlights the critical role of the intrinsically disordered AB region in modulating the structural and functional properties of hRXRγ, including its ability to oligomerize, its overall stability, and conformation heterogeneity. The AB region does not act as an independent unit but amalgamates with the rest of the receptor, which fine-tunes the structural variability of hRXRγ, making it responsive to environmental conditions. These findings highlight the AB region as a critical determinant of hRXRγ's structural features and, potentially, its transcriptional potential.
人类维甲酸X受体γ（hRXRγ）是三种已被鉴定的RXR亚型之一，属于核受体超家族的转录因子。所有RXR亚型都具有几乎相同的结构元件，包括一个保守的DNA结合结构域、一个D区域、一个配体结合结构域和一个F区域。然而，每个亚型都有一个独特的N端AB区域，该区域通过其参与蛋白质-蛋白质相互作用的非配体依赖性激活功能，以细胞和启动子依赖的方式调节靶基因的转录激活。尽管AB区域具有功能重要性，但其结构贡献，特别是在全长受体的背景下，在很大程度上仍未被探索。在这里，我们揭示了hRXRγ的AB区域在调节受体分子特性中的作用。对全长受体（hRXRγ）和缺乏AB区域的缺失突变体（ΔABhRXRγ）的比较分析突出了内在无序的AB区域在调节hRXRγ的结构和功能特性中的关键作用，包括其寡聚化能力、整体稳定性和构象异质性。AB区域不是作为一个独立的单元起作用，而是与受体的其余部分融合，从而微调hRXRγ的结构变异性，使其对环境条件作出反应。这些发现突出了AB区域是hRXRγ结构特征以及潜在的转录潜能的关键决定因素。
