重新定位核受体用于对联体反应的液态凝聚物形成和基因调节
Erik Rihtar1, Tina Fink1,2, Filip Ivanovski1,2
1Department of Synthetic Biology and Immunology, National Institute of Chemistry, Ljubljana, Slovenia.
Nature communications
|January 31, 2026
概括
研究人员使用核受体开发了新的激素反应化学诱导二分化 (CID) 系统. 这些系统通过可调节的液态液相分离 (LLPS) 凝结物控制基因表达,从而使先进的合成生物学应用成为可能.
科学领域:
- 合成生物学 合成生物学
- 分子生物学分子生物学
- 生物化学 生化学
背景情况:
- 细胞过程依赖于蛋白质相互作用网络.
- 现有的化学诱导二分化 (CID) 系统因其对外部分子的反应而受到限制,阻碍了与自然细胞信号通路的整合.
研究的目的:
- 通过重新定位核受体 (NR) 连接体结合域 (LBD) 和协同激活剂,开发新型激素或药物响应的CID系统.
- 为增强转录控制,设计激素反应的液态液相分离 (LLPS) 凝聚物.
主要方法:
- 从TRβ,VDR,RARγ,ERβ和GR2中利用LBD与TIF2联合激活来构建CID.
- 设计的CIDs对特定的激素 (例如,三甲氨酸,维生素D,视网酸,雌激素,皮质醇) 和它们的对抗剂有反应.
- 开发了激素响应的LLPS凝聚物用于转录放大.
主要成果:
- 成功创建了对一系列激素和药物有反应的CID.
- 证明这些CID可以作为两输入的转录开关来实现精确的基因调节.
- 使用激素响应的LLPS凝聚剂实现显著的转录放大 (高达几百倍).
结论:
- 重新设计的NR LBD为创建内源性联结体响应性CID系统提供了一个多功能平台.
- 激素控制的LLPS冷凝剂提供了一个可调节的机制,用于强大的转录控制.
- 这种方法将合成生物学与生理信号联系起来,为基因电路,生物传感和治疗开辟了道路.
相关概念视频
00:49Ligand Binding and Linkage
5.6K
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
5.6K
01:10C–C Bond Formation: Aldol Condensation Overview
16.3K
Aldol condensation is an important route in synthetic organic chemistry used to generate a new carbon–carbon bond under basic or acidic conditions. The aldol condensation reaction presented in Figure 1 constitutes an aldol addition reaction followed by the dehydration process.
16.3K
01:31Internal Receptors
74.7K
Many cellular signals are hydrophilic and therefore cannot pass through the plasma membrane. However, small or hydrophobic signaling molecules can cross the hydrophobic core of the plasma membrane and bind to internal, or intracellular, receptors that reside within the cell. Many mammalian steroid hormones use this mechanism of cell signaling, as does nitric oxide (NO) gas.
74.7K
01:45Regulation of Nuclear Protein Sorting
3.3K
Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
3.3K
02:39Phase Transitions: Vaporization and Condensation
21.3K
The physical form of a substance changes on changing its temperature. For example, raising the temperature of a liquid causes the liquid to vaporize (convert into vapor). The process is called vaporization—a surface phenomenon. Vaporization occurs when the thermal motion of the molecules overcome the intermolecular forces, and the molecules (at the surface) escape into the gaseous state. When a liquid vaporizes in a closed container, gas molecules cannot escape. As these gas phase molecules...
21.3K
01:31Transducer Mechanism: Nuclear Receptors
2.5K
Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
2.5K