酸化基因决定了GPCR的C端域构造和阿雷斯相互作用
Myriam Guillien1, Assia Mouhand1, Amin Sagar1
1Centre de Biologie Structurale (CBS), CNRS, University Montpellier, Inserm, Montpellier, France.
Structure (London, England : 1993)
|September 5, 2023
概括
化G蛋白结合受体 (GPCRs) 诱导其C端区域的结构变化,有利于阿雷斯结合. 这种依赖酸化的结构调节了arrestin结合和下游信号结果.
科学领域:
- 分子和细胞生物学分子和细胞生物学
- 生物化学 生物化学
- 药理学 药理学是指药理学的学科.
背景情况:
- G蛋白结合受体 (GPCR) 信号由C端域酸化调节.
- 确切的分子机制控制arrestin:GPCR相互作用仍然不完全理解.
- 对于各种生理过程来说,arrestin依赖性途径至关重要.
研究的目的:
- 为了研究酸化对GPCRC终端区域的结构动态的影响.
- 阐明酸化如何影响GPCRs和逮捕因之间的相互作用.
- 探索这些相互作用在停止依赖信号传输中的作用.
主要方法:
- 使用了三种类似于罗多普辛的GPCR的相仿变体:血管压素V2受体 (V2R),1a型格林受体 (GHSR) 和β2-上腺素受体 (β2AR).
- 分析了GPCRC终端区域的结构特征.
- 评估了酸化对阿雷斯-2结合的作用.
主要成果:
- 在GPCR的C端区域内确定了预成型的二次结构元素和短线形图案 (SLiM).
- 证明酸化会在这些SLiM中诱导特定的形状转变.
- 观察到,这些酸化诱导的形状变化有利于阿斯特林-2的结合.
结论:
- 化GPCR的C端区域促进了结构化,为逮捕素创造了有利的结合点.
- 这种依赖酸化的结构是调节阿雷斯结合亲和力的关键机制.
- 这些发现提出了一个模型,其中GPCR的C端形状决定了接触和随后的信号的停止.
相关概念视频
Assembly of Signaling Complexes
5.8K
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,...
5.8K
Amplifying Signals via Enzymatic Cascade
8.5K
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
8.5K
Activation and Inactivation of G Proteins
7.2K
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...
7.2K
GPCRs Regulate Adenylyl Cylase Activity
5.7K
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...
5.7K
IP3/DAG Signaling Pathway
12.2K
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...
12.2K
GPCR Desensitization
6.1K
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...
6.1K


