在细胞癌的癌症驱动因素的蛋白质蛋白相互作用的计算分析
Jimin Pei1,2,3, Jing Zhang1,2,3, Qian Cong1,2,3
1Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA.
FEBS open bio
|November 15, 2023
概括
深度学习预测了癌驱动因素的蛋白质相互作用,揭示了突变对蛋白质结合的影响. 这些发现突显了细胞癌 (RCC) 发病过程中的关键突变,并提出了新的治疗点.
科学领域:
- 在瘤学瘤学.
- 结构生物学 结构生物学
- 计算生物学 计算生物学
背景情况:
- 细胞癌 (RCC) 是最常见的癌,发病率越来越高.
- RCC的发展与各种癌症驱动蛋白有关,这些蛋白质通常由瘤抑制基因编码.
- 这些驱动因素参与了关键的细胞过程,如蛋白质降解,染色质重塑和转录.
研究的目的:
- 使用深度学习预测RCC驱动蛋白的蛋白质与蛋白质相互作用 (PPI).
- 获得对RCC驱动复合体的结构洞察力,并确定潜在的药物点.
- 分析癌症体质突变对涉及RCC驱动器的PPI的影响.
主要方法:
- 利用包括AlphaFold在内的深度学习模型来预测蛋白质与蛋白质相互作用 (PPI).
- 预测涉及关键RCC驱动因素的高可信度蛋白质复合体 (例如,TCEB1,KMT2C/D,KDM6A,TSC1,TRRAP).
- 将RCC基因组测序数据的癌症体质误解突变映射到预测和实验PPI接口.
主要成果:
- 为多个RCC驱动器的复合体生成了高可靠性的结构预测.
- 确定了特定的相互作用接口,如NRF2-MAFK,作为潜在的药物设计目标.
- 观察到100多种癌症体质突变,影响了涉及VHL和TCEB的复合体的结合亲和力1.1.
结论:
- 预测的PPI提供了对RCC病原性有价值的结构性见解.
- 影响驱动蛋白复合体结合亲和力的突变在RCC中显著.
- 这些发现可能为细胞癌的新型向疗法铺平道路.
相关概念视频
02:04Protein-protein Interfaces
12.5K
Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...
12.5K
02:26Protein Networks
4.0K
An organism can have thousands of different proteins, and these proteins must cooperate to ensure the health of an organism. Proteins bind to other proteins and form complexes to carry out their functions. Many proteins interact with multiple other proteins creating a complex network of protein interactions.
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
4.0K
03:03mTOR Signaling and Cancer Progression
3.8K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.8K
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
7.4K
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
7.4K
01:20The Retinoblastoma Gene
4.1K
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
4.1K