CAND1 抑制了库林-2-RING 基因酶,从而增强了基质特异性
Kankan Wang1, Stephanie Diaz1,2, Lihong Li1,3
1Department of Biochemistry, Purdue University, West Lafayette, IN, USA.
Nature structural & molecular biology
|January 4, 2024
概括
库林-2 (CUL2) 酶是蛋白质降解和药物发现的关键. 新的发现表明,CAND1抑制了CUL2介导的降解,使得可选择性蛋白质向用蛋白质分解向奇默体 (PROTAC) 药物.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
背景情况:
- 库林-2 (CUL2) - 环泛素连接酶 (CRL2s) 对于泛素化和向蛋白解的奇米拉 (PROTAC) 药物发现至关重要.
- 基于库林-1 (CUL1) 的CRL1s被CAND1激活,这促进了动态组合和基质受体交换.
研究的目的:
- 调查CAND1在CRL2介导的蛋白质降解中的作用.
- 阐明CAND1影响CRL2活动和基质向的机制.
主要方法:
- 研究了CAND1对人类细胞中CRL2介导的蛋白质降解的影响.
- 分析了CAND1与CRL2VHL复合物的结合动力学.
- 使用PROTAC来招募新基质到CRL2VHL并评估降解选择性.
主要成果:
- 发现CAND1可以抑制CRL2介导的蛋白质降解.
- CAND1显著增加了CRL2s的解离率,同时对它们的组装产生最小的影响.
- 由于CAND1的抑制作用,可以根据它们与CRL2s的亲和关系来区分标蛋白.
结论:
- CAND1作为CRL2介导的蛋白质降解的抑制剂.
- 该机制涉及改变结合动力学,特别是增加解离率.
- 这为使用PROTACs在细胞环境中的选择性蛋白质降解节奏提供了一种新的策略.
相关概念视频
Anaphase Promoting Complex
2.9K
The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
2.9K
Covalently Linked Protein Regulators
6.8K
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
These groups modify specific amino acids in a protein....
6.8K
Inhibition of Cdk Activity
4.8K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.8K
Regulated Protein Degradation
7.3K
It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
7.3K
Protein Complexes with Interchangeable Parts
2.5K
Groups of proteins may form a complex where each protein in this complex has a different role in the overall execution of the complex’s function. Often some of the proteins in the complex can be replaced by a closely related variant to give a complex that contains many of the same components yet is functionally distinct.
The SCF ubiquitin ligase is a protein complex of five individual proteins. This complex attaches ubiquitin to other target proteins to mark them for degradation. In order...
The SCF ubiquitin ligase is a protein complex of five individual proteins. This complex attaches ubiquitin to other target proteins to mark them for degradation. In order...
2.5K
Positive Regulator Molecules
5.5K
Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
5.5K


