根据NPC1和NPC2的低pH依赖性溶酶体胆固醇的结构基础
Hongwu Qian1, Xuelan Wu2, Ximing Du3
1Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Cell
|June 17, 2020
概括
在NPC1和NPC2蛋白质的缺陷导致尼曼-皮克疾病类型C (NPC). 这项研究揭示了从NPC2到NPC1转移胆固醇的低pH机制,这对溶解体胆固醇的退出至关重要.
科学领域:
- 细胞生物学
- 结构生物学
- 生物化学
背景情况:
- 溶解体胆固醇的退出对于细胞平衡至关重要.
- 在NPC1和NPC2蛋白质的缺陷导致尼曼·皮克病C型 (NPC).
- 了解胆固醇运输的分子机制至关重要.
研究的目的:
- 阐明低pH依赖胆固醇从NPC2转移到NPC1的结构基础.
- 描述参与胆固醇排出的NPC1的结构动态.
主要方法:
- 低温电子显微镜 (Cryo-EM) 在不同的pH值 (8.0和5.5).
- 在纳米磁盘和洗剂中确定NPC1的结构.
- 对NPC1-NPC2复合物的结构分析.
主要成果:
- NPC1具有连接N端域 (NTD) 和固醇感应域 (SSD) 的道.
- 低pH诱导NPC1的NTD的结构变化,促进胆固醇的转移.
- 在道的膜边界观察到一个假定的胆固醇分子.
- NPC1-NPC2复合体的结构揭示了胆固醇转移的分子细节.
结论:
- 这项研究提供了关于溶酶体胆固醇退出机制的原子层次见解.
- 结构性表征揭示了NPC1如何促进NPC2的胆固醇运输.
- 这些发现有助于更好地了解NPC疾病的发病因子和潜在的治疗点.
相关概念视频
Regulation of Nuclear Protein Sorting
3.1K
Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
3.1K
Receptor-mediated Endocytosis
109.9K
Overview
109.9K
Receptor-mediated Endocytosis
7.3K
Receptor-mediated endocytosis is when bulk amounts of specific molecules are imported into a cell after binding to cell surface receptors. The molecules bound to these receptors are taken into the cell through inward folding of the cell surface membrane, which is eventually pinched off into a vesicle within the cell. Structural proteins, such as clathrin, coat the budding vesicle.
Clathrin-Mediated Endocytosis of LDL
One well-characterized example of receptor-mediated endocytosis is the...
Clathrin-Mediated Endocytosis of LDL
One well-characterized example of receptor-mediated endocytosis is the...
7.3K
The Early Endosome: Endocytosis of Transferrin
4.5K
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...
4.5K
Nuclear Protein Sorting
6.0K
Nuclear protein sorting is the selective trafficking of histones, polymerases, gene regulatory proteins into the nucleus and exporting RNAs and ribosomes to the cytosol. It is a tightly controlled process that regulates gene expression within a cell.
Proteins targeted to the nucleus carry nuclear localization signals or NLS recognized by import receptors in the cytosol. Similarly, proteins with nuclear export signals are recognized by export receptors. Import and export receptors are...
Proteins targeted to the nucleus carry nuclear localization signals or NLS recognized by import receptors in the cytosol. Similarly, proteins with nuclear export signals are recognized by export receptors. Import and export receptors are...
6.0K
Synthesis of Phosphatidylcholine in the ER Membrane
3.9K
The ER synthesizes lipids for building cell membranes and performing cellular functions such as energy storage and signaling. The lipid synthesis machinery embedded in the ER membrane primarily collects all reactants from the cytosol. Following synthesis, the secretory pathway and the ER contact sites distribute these lipids to other cellular organelles. Additionally, the energy-rich triacylglycerides are transported from the ER via lipid droplets.
The major components of all eukaryotic cell...
The major components of all eukaryotic cell...
3.9K


