克洛斯特里破坏肠毒素的冷EM结构与其人类受体,Claudin-4相结合
bioRxiv : the preprint server for biology
|July 19, 2024
概括
致病性Clostridium perfringens肠毒素 (CpE) 通过结合Claudin-4形成致命的毛孔. 这项研究揭示了CpE-claudin-4复杂结构,为孔隙组装和潜在的治疗策略提供了洞察力.
科学领域:
- 微生物学 微生物学
- 结构生物学 结构生物学
- 生物化学 生物化学
背景情况:
- 病原性Clostridium perfringens产生肠毒素 (CpE),是人类和动物严重胃肠道疾病的主要原因.
- CpE的目标是claudins,这些蛋白质在肠表皮形成紧密的接口,破坏正常功能.
- CpE劫持了claudins,形成了小的复合物,这些复合物是细胞毒性β-桶孔的前体.
研究的目的:
- 确定CPE与其人类受体Claudin-4的复合体中的高分辨率结构.
- 阐明CpE-克劳丁复合物的形成和随后的孔隙组装的分子机制.
- 确定预防CPE诱导的细胞毒性和治疗相关胃肠道疾病的策略.
主要方法:
- 低温电子显微镜 (cryo-EM) 用于以4.0和2.8 Å分辨率获得CPE-claudin-4复合物的结构.
- 结构分析侧重于小型复杂的架构,结合接口,以及CpE诱导的Claudin-4的变化.
- 研究了对从小复合体过渡到β-桶孔的生物物理见解.
主要成果:
- 这些结构揭示了claudin-4/CpE小复合物的详细结构,包括关键的结合残留物.
- 解决了CPE与肠膜相对的方向,以及CpE诱导的Claudin-4的结构变化.
- 这项研究提供了复合物的动力捕获状态的证据,并暗示了贝塔桶孔形成的机制,涉及素.
结论:
- 这项工作为克劳丁结合的CPE提供了前所未有的结构细节,澄清了其孔隙组装机制.
- 了解CPE-克劳丁相互作用和毛孔形成途径,为开发新疗法开辟了道路.
- 准CpE毛孔组合是一个有前途的策略,用于对抗CpE介导的胃肠道疾病.
更多相关视频
09:25Do's and Don'ts of Cryo-electron Microscopy: A Primer on Sample Preparation and High Quality Data Collection for Macromolecular 3D Reconstruction
Published on: January 9, 2015
46.1K
11:33Using Tomoauto: A Protocol for High-throughput Automated Cryo-electron Tomography
Published on: January 30, 2016
10.9K
相关概念视频
Cryo-electron Microscopy
3.3K
Conventional electron microscopy (EM) involves dehydration, fixation, and staining of biological samples, which distorts the native state of biological molecules and results in several artifacts. Also, the high-energy electron beam damages the sample and makes it difficult to obtain high-resolution images. These issues can be addressed using cryo-EM, which uses frozen samples and gentler electron beams. The technique was developed by Jacques Dubochet, Joachim Frank, and Richard Henderson, for...
3.3K
Clathrin Coated Vesicles
6.9K
Clathrin-coated vesicles use endocytosis to transport receptors and lysosomal hydrolases from the Golgi to the lysosome in the late secretory pathway. Clathrin-mediated endocytosis was the first described endocytic process, and Clathrin-coated vesicles remain one of the most well-studied transport vesicles. The molecular machinery that generates clathrin-coated vesicles comprises over 50 proteins that precisely coordinate vesicle formation. Cell surface receptors concentrated in indented sites...
6.9K
Tight Junctions
5.2K
Tight junctions are molecular seals between cells that prevent the leaking of fluids, ions, and other small solutes across cavities and compartments in multicellular organisms. They are mainly composed of claudin and occludin transmembrane proteins, and other proteins such as tricellulin and JAM (junctional adhesion molecule). All these proteins are 4-pass transmembrane proteins, except JAM, which is a single-pass transmembrane protein belonging to the immunoglobulin superfamily. The...
5.2K
Structure of Cadherins
3.3K
The cadherins were one of the first cell adhesion molecules discovered; the term “cadherins” is based on their calcium-dependent adhering properties. The first cadherins discovered on the epithelial, neuronal, and placental cells were named E-cadherin, P-cadherin, and N-cadherin, respectively. These classical cadherins share sequence and structural similarities. Other cadherins, including those involved in cell signaling, are grouped into non-classical cadherins. This...
3.3K
Fusion of Secretory Vesicles with the Plasma Membrane
11.0K
Proteins and neurotransmitters in secretory vesicles can be released from a cell upon vesicle docking, priming, and fusion with the plasma membrane. Vesicles are docked and primed in preparation for the quick exocytosis of their contents in response to a stimulus. The fusion process is mainly carried out by a SNAP Receptor or SNARE complex, consisting of synaptobrevin, syntaxin-1, and SNAP-25.
In 1993, Jim Rothman proposed that the antiparallel pairing of vesicular and transmembrane SNAREs, or...
In 1993, Jim Rothman proposed that the antiparallel pairing of vesicular and transmembrane SNAREs, or...
11.0K
