β-阿雷斯与甲基增生谷氨酸受体mGlu3的合的分子基础
Tianlei Wen1, Mei Du2, Yue Lu1
1State Key Laboratory of Medicinal Chemical Biology and Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, China.
Nature chemical biology
|March 6, 2025
概括
我们阐明了二度家族C GPCRs,如甲基胺基基因受体3 (mGlu3) 如何与β-arrestins (βarrs) 相互作用. 结构显示βarr1结合稳定了mGlu3在非活性状态,这对受体调节至关重要.
科学领域:
- 结构生物学 结构生物学
- 神经科学是一个神经科学.
- 生物化学 生物化学
背景情况:
- β-Arrestins (βarrs) 是G蛋白结合受体 (GPCR) 信号传递的关键调节者.
- 通过二度家族C GPCRs招募阿雷斯的机制尚不清楚.
研究的目的:
- 确定β-arrestin 1 (βarr1) 与二次性甲基基质酸盐受体亚型3 (mGlu3) 的相互作用的结构基础.
- 阐明C家族GPCRs的β-arr介导失活的分子机制.
主要方法:
- 进行X射线晶体学,以获得mGlu3-βarr1复合物的结构.
- 分析蛋白质-蛋白质相互作用和形状变化.
主要成果:
- 在2:1和2:2静脉测量中确定了与βarr1结合的mGlu3二元体的两个结构.
- 与L-氨酸结合的mGlu3二聚体在βarr1参与时采用了非活性构造.
- 确定了涉及mGlu3跨膜域,细胞内循环,C端尾酸化部位和βarr1的特定相互作用.
- βarr1结合稳定了一个不活跃的mGlu3二维接口.
结论:
- arr1结合锁定mGlu3进入无活体构造,为C家族GPCRs的无活化提供结构基础.
- 这项研究为管理GPCR脱敏和调节的分子机制提供了关键的见解.
相关概念视频
GPCR Desensitization
5.7K
G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
5.7K
Assembly of Signaling Complexes
5.7K
Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
5.7K
Ligand-Gated Ion Channel Receptor: Gating Mechanism
2.1K
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...
2.1K
G-protein Coupled Receptors
114.2K
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
114.2K
Activation and Inactivation of G Proteins
6.5K
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
6.5K
IP3/DAG Signaling Pathway
11.8K
Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
11.8K


