低温电磁检测显示通过集成蛋白介导的TGF-β激活而没有从潜伏的TGF-β释放
Melody G Campbell1, Anthony Cormier2, Saburo Ito2
1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
Cell
|January 21, 2020
概括
集成蛋白αvβ8特别结合潜伏转化生长因子-β (L-TGF-β),这是激活这种生长因子的关键步骤. 通过阻断免疫抑制T细胞活动,了解这种相互作用为癌症提供了新的治疗策略.
科学领域:
- 分子和细胞生物学
- 免疫学
- 结构生物学
背景情况:
- 在激活潜伏转化生长因子-β (L-TGF-β) 方面,整合素αvβ8起着至关重要的作用.
- 这种激活过程对于免疫抑制调节T细胞的分化至关重要.
- 抑制αvβ8介导的TGF-β激活是一种潜在的癌症治疗策略.
研究的目的:
- 阐明αvβ8与L-TGF-β的结合特异性的结构基础.
- 了解由αvβ8激活L-TGF-β的机制.
- 确定治疗αvβ8活性的结构标.
主要方法:
- 低温电子显微镜 (cryo-EM) 用于确定高分辨率结构.
- 结构引导的突变发生以探测结合相互作用.
- 基于细胞的测试以验证功能后果.
主要成果:
- 详细的结构洞察到αvβ8ectodomain与完整的L-TGF-β的结合.
- 两种不同的抑制抗体片段的相互作用的特征.
- 揭示了L-TGF-β复合体内发生的TGF-β激活的新机制.
结论:
- 这项研究提供了对αv8-介导的TGF-β激活的机制理解.
- 结构数据为开发针对αvβ8的向治疗提供了合理的基础.
- 这种途径的抑制可以通过影响调节T细胞来调节瘤微环境.
相关概念视频
Activation of Integrins
4.8K
Integrins bind ligands and transmit information from outside the cell to inside or vice-versa through an "outside-in signaling" or "inside-out signaling."
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding...
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding...
4.8K
TGF - β Signaling Pathway
10.3K
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
10.3K
Intracellular Signaling Affects Focal Adhesions
3.4K
Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...
Some...
3.4K
Integrins
5.1K
Animal and protozoan cells do not have cell walls to help maintain shape and provide structural stability. Instead, these eukaryotic cells secrete a sticky mass of carbohydrates and proteins into the spaces between adjacent cells. This network of proteins and molecules is called an extracellular matrix or ECM.
Some ECM proteins assemble into a basement membrane to which the remaining components adhere. Proteoglycans typically form the bulk of the ECM while fibrous proteins, like collagen,...
Some ECM proteins assemble into a basement membrane to which the remaining components adhere. Proteoglycans typically form the bulk of the ECM while fibrous proteins, like collagen,...
5.1K


