通过optineurin识别活性Rab8a的分子基础
Jing Zhang1, Lei Liu1, Miao Li2
1College of Chemistry and Materials Science, Sichuan Normal University, Chengdu, Sichuan 610068, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China.
Journal of molecular biology
|October 7, 2024
概括
奥普丁氨氨酸 (OPTN) 通过其氨酸-拉链域结合活性Rab8a,澄清了它在细胞过程和肌缩性侧面硬化症 (ALS) 疾病机制中的作用.
科学领域:
- 分子生物学分子生物学
- 结构生物学 结构生物学
- 细胞生物学 细胞生物学
背景情况:
- 奥普丁尿素 (OPTN) 是一种多功能适应蛋白,对囊泡贩运和自至关重要.
- OPTN突变与人类疾病有关,包括肌缩性侧面硬化症 (ALS).
- 通过OPTN促进Rab8a被TBC1D17无活化的机制尚不清楚.
研究的目的:
- 在生物化学和结构上描述OPTN和Rab8a之间的相互作用.
- 阐明OPTN与Rab8a的结合机制,以及Rab8a与效应器的独特结合模式.
- 研究涉及OPTN,Rab8a和TBC1D17.的三元复合体的形成.
主要方法:
- 生物化学测定 生物化学测定
- 在X射线晶体学.
- 结构分析 结构分析
主要成果:
- OPTN通过其氨酸拉链域 (LZD) 选择性地识别了与GTP结合的活性Rab8a.
- OPTN LZD/Rab8a复合体的晶体结构揭示了详细的结合相互作用.
- 证明了OPTN,Rab8a和TBC1D17的三元复合体,涉及OPTN的中央卷轴-卷轴域.
结论:
- 提供了对OPTN-Rab8a相互作用的机制见解.
- 这项研究扩大了对Rab8a效应器结合模式的理解.
- 这些发现提供了对OPTN突变相关疾病 (如ALS) 的病因学的见解.
相关概念视频
Rab Proteins
3.9K
Rab proteins constitute the largest family of monomeric GTPases, of which 70 members are present in humans. Rab proteins and their effectors regulate consecutive stages of vesicle transport such as vesicle transport, docking, and fusion to the correct recipient membrane.
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...
3.9K
Rab Cascades
2.6K
Rab GTPases act in a regulated cascade during membrane fusion, helping the lipid bilayers mix. The Rab family of proteins are active when bound to GTP, and inactive when bound to GDP. Hence, they act as guanine nucleotide-dependent molecular switches. Rab-GTP recognizes and binds to long or short-range tethering proteins to capture the target vesicle. These tethers coordinate with SNAREs on the vesicle and the target membrane to assemble the trans SNARE complex that locks the mixing bilayers.
2.6K
Pinching-off of Coated Vesicles
3.1K
Vesicle budding is orchestrated by distinct cytosolic proteins such as adaptor proteins, coat proteins, and GTPases. To initiate vesicle budding, membrane-bending proteins containing crescent-shaped BAR domains bind to the lipid heads in the bilayer and distort the membrane to form a protein-coated vesicle bud. Adaptors proteins such as AP2 for clathrin-coated vesicles can nucleate on the deformed membrane. Finally, coat proteins such as clathrin or COPI and COPII assemble into a coat forming...
3.1K
Directing Proteins to the Rough Endoplasmic Reticulum
7.2K
The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...
7.2K
Export of Misfolded Proteins out of the ER
3.5K
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...
3.5K
The Early Endosome: Endocytosis of Transferrin
3.2K
Essential proteins such as insulin or low-density lipoprotein (LDL) and micronutrients such as iron enter a eukaryotic cell through receptor-mediated endocytosis. Subsequently, the early endosomes fuse with the vesicles containing such receptor-ligand complexes and play a vital role in sorting the incoming ligands and receptors. While the ligands are either degraded inside the vesicle or released into the cytosol, their receptors are returned to the plasma membrane for further rounds of...
3.2K


