相关实验视频
Updated: May 17, 2025

10:56
Assays for the Degradation of Misfolded Proteins in Cells
Published on: August 28, 2016
11.9K
通过TRIM2121进行化学诱导的核孔复杂蛋白质降解
Xiaomei Li1, Qingyang Wang1, Anping Guo1
1HitGen Inc., Chengdu, Sichuan 610200, China.
ACS chemical biology
|April 18, 2025
概括
研究人员使用DNA编码图书馆技术发现了TRIM21 E3酶的新型小分子配体. 这些配体降解核孔复合蛋白质,通过核包膜破坏导致癌细胞死亡.
科学领域:
- 生物化学 生化学
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 双功能降解分子,如蛋白质解析向化体 (PROTACs),显示出希望,但受到E3酶连接体稀缺性的限制.
- TRIM21是一种E3结合酶,具有潜在的治疗应用.
研究的目的:
- 为了识别E3结合酶TRIM21的新型小分子结合体.
- 研究这些TRIM21配体的作用机制和细胞效应.
主要方法:
- 用DNA编码图书馆 (DEL) 技术来发现连接体.
- 结晶学证实了连接体-TRIM21的相互作用.
- 蛋白质组学研究以确定蛋白质标.
- 免疫光测试以评估细胞效应.
主要成果:
- 确定了TRIM21.21的新型小分子配体.
- 在癌症细胞类型中证明了连接体的抗增殖作用.
- 发现连接体下调节核孔复合蛋白NUP155和mRNA出口因子GLE1在TRIM21依赖的,全方位蛋白蛋白酶路径中.
- 显示的NUP155是主要目标,GLE1是乘客目标.
- 证实NUP155和GLE1的降解破坏了核外的完整性,导致细胞死亡.
结论:
- 使用DEL技术发现了新的TRIM21配体.
- TRIM21配体作为单价降解剂,诱导NUP155和GLE1.1的降解.
- 这些蛋白质的降解导致核外破坏和细胞死亡,揭示了TRIM21配体的新作用模式.
相关概念视频
Regulation of Nuclear Protein Sorting
2.3K
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...
2.3K
Nuclear Protein Sorting
4.4K
Nuclear protein sorting is the selective trafficking of histones, polymerases, gene regulatory proteins into the nucleus and exporting RNAs and ribosomes to the cytosol. It is a tightly controlled process that regulates gene expression within a cell.
Proteins targeted to the nucleus carry nuclear localization signals or NLS recognized by import receptors in the cytosol. Similarly, proteins with nuclear export signals are recognized by export receptors. Import and export receptors are...
Proteins targeted to the nucleus carry nuclear localization signals or NLS recognized by import receptors in the cytosol. Similarly, proteins with nuclear export signals are recognized by export receptors. Import and export receptors are...
4.4K
Export of Misfolded Proteins out of the ER
3.4K
After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
3.4K
Nuclear Export of mRNA
7.5K
Before mRNAs are exported to the cytoplasm, it is crucial to check each mRNA for structural and functional integrity. Eukaryotic cells use several different mechanisms, collectively known as mRNA surveillance, to look for irregularities in mRNAs. Irregular or aberrant mRNA are rapidly degraded by various enzymes. If a defective mRNA escapes the surveillance, it would be translated into a protein which would either be non-functional or not function properly. One of the primary irregularities in...
7.5K
The Unfolded Protein Response
4.3K
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
4.3K
Protein Translocation Machinery on the ER Membrane
4.3K
The translocon complex situated on the ER membrane is the main gateway for the protein secretory pathway. It facilitates the transport of nascent peptides into the ER lumen and their insertion into the ER membrane.
Sec61 protein conducting channel
In eukaryotes, the translocon complex comprises a core heterotrimeric translocator channel called the Sec61 complex. This channel includes three transmembrane proteins, Sec61α, Sec61β, and Sec61γ, and is the largest subunit of the...
Sec61 protein conducting channel
In eukaryotes, the translocon complex comprises a core heterotrimeric translocator channel called the Sec61 complex. This channel includes three transmembrane proteins, Sec61α, Sec61β, and Sec61γ, and is the largest subunit of the...
4.3K

