在ClC-3交换器中,腺因核酸调节和神经退行性病理的结构基础
Yangzhuoqun Wan1,2, Shuangshuang Guo1,2, Wenxuan Zhen1,2
1Department of Biophysics and Disease Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Nature communications
|August 6, 2024
概括
这是一个ClC-3化物/质子交换器.
科学领域:
- 生物化学和结构生物学.
- 神经科学是一个神经科学.
- 分子生物学分子生物学
背景情况:
- 化物/质子交换器ClC-3对于生理功能至关重要,并与神经退行性疾病有关.
- ATP增强ClC-3以感知代谢能量,但其由腺因核酸的差异调制以及功能获取突变的机制尚不清楚.
研究的目的:
- 阐明 ClC-3 的腺因核酸调节的基础结构机制.
- 研究导致神经退行性疾病的ClC-3中功能增益突变的结构基础.
主要方法:
- 高分辨率冷电子显微镜 (cryo-EM) 用于确定野生型和突变型ClC-3的结构.
- 补丁电灯的记录,以评估离子运输.
- 分子动力学 (MD) 模拟来分析核酸结合和构造变化.
主要成果:
- 确定野生型ClC-3 (apo,ATP,ADP,AMP结合) 和I607T突变体 (apo,ATP结合) 的结构.
- 揭示了腺核酸如何与ClC-3结合并改变离子占用率.
- 观察到I607T突变诱导的形状变化导致增强电流.
结论:
- 建立了ClC-3的腺因核酸调节的结构基础.
- 提供了关于ClC-3在神经退行性疾病中的作用的见解.
- 确定了治疗ClC-3介导的神经退行性疾病的潜在药物标.
相关概念视频
Ligand-Gated Ion Channel Receptor: Gating Mechanism
2.2K
Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...
2.2K
Ligand-gated Ion Channels
12.3K
Ligand-gated ion channels are transmembrane proteins with a channel for ions to pass through and a binding site for a ligand. The channel opens only when a ligand attaches to the binding site.
Three Subfamilies of Ligand-gated Ion Channels
Ligand-gated ion channels fall into three subfamilies. The 'Cys-loop' includes the nicotinic acetylcholine receptors, γ-aminobutyric acid (GABA), glycine, and 5-hydroxytryptamine receptors. The second one is the 'Pore-loop' channels that...
Three Subfamilies of Ligand-gated Ion Channels
Ligand-gated ion channels fall into three subfamilies. The 'Cys-loop' includes the nicotinic acetylcholine receptors, γ-aminobutyric acid (GABA), glycine, and 5-hydroxytryptamine receptors. The second one is the 'Pore-loop' channels that...
12.3K
Allosteric Proteins-ATCase
5.7K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.7K
Lysosomal Hydrolases
3.8K
Lysosomes are the site for the degradation of macromolecules and biological polymers released during membrane trafficking events such as secretory, endocytic, autophagic, and phagocytic pathways. The membrane-enclosed area of the lysosome, called the lumen, contains hydrolytic enzymes active in an acidic environment. These acid hydrolases are functional at a pH between 4.5 and 5 and are involved in cellular processes such as cell signaling, energy metabolism, restoration of the plasma membrane,...
3.8K
ATP Synthase: Mechanism
14.3K
In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
14.3K
GPCRs Regulate Adenylyl Cylase Activity
5.4K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
5.4K


