脊椎核磁共振显示β1上腺体受体中的异质信号传导网络
Shin Isogai1, Xavier Deupi2, Christian Opitz1
1Focal Area Structural Biology and Biophysics, Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
Nature
|February 4, 2016
概括
核磁共振 (NMR) 揭示了火β-1上腺素受体 (β1AR) 的详细动态. 结合激素诱导特定位点的运动,这对于理解G蛋白合受体 (GPCR) 信号传导至关重要.
科学领域:
- 生物化学
- 结构生物学
- 药理学
背景情况:
- G蛋白结合受体 (GPCRs) 是重要的细胞信号蛋白,但它们的动态,联体诱导的信号转导仍然不太清楚,尽管结构生物学有进展.
- 现有的方法对真核 GPCR 提供有限的动态信息,阻碍了对其功能的完全理解.
研究的目的:
- 使用NMR光谱学研究热稳定的火β-1上腺素受体 (β1AR) 中联体诱导信号转导的动态机制.
- 确定涉及GPCR全激活的关键残留物和途径.
主要方法:
- 在真核表达系统中使用[(15) N]氨酸标记来获得热稳定β1AR突变的高分辨率NMR数据.
- 分析了6个配体复合体和apo形式的NMR光谱,以映射受体动态和突变的影响.
主要成果:
- 在结合口附近观察到异质的受体运动,转移到细胞内TM5螺旋的同质读数,与连接剂有效性相关.
- 确定了对G蛋白模拟纳米体 (NB80) 结合和G蛋白激活至关重要的保存型氨酸 (Y227和Y343).
- 证明NB80结合会诱导整个受体的显著光谱变化,这表明G蛋白类伙伴对完全激活的重要性.
结论:
- 核磁共振光谱提供了一种强大的方法,以高分辨率划分GPCR信号传输网络.
- 这项研究阐明了β1AR的全激活途径中的关键联系,强调了特定残留物在信号传导中的作用.
- 与NMR结合的热稳定GPCR突变为研究受体动力学和激活机制提供了一种一般方法.
相关概念视频
Adrenergic Receptors: β Subtype
4.4K
β-adrenoceptors have varied sensitivities towards adrenaline, noradrenaline, and isoprenaline. The order of agonist potency is as follows:
Isoprenaline > Adrenaline > Noradrenaline
Neurotransmitter binding to these receptors causes activation of adenylyl cyclase resulting in increased concentrations of cAMP and modulation of calcium ion channels within the cell. They are further classified into β1, β2, and β3 subtypes.
β1-adrenoceptors: β1-adrenoceptors...
Isoprenaline > Adrenaline > Noradrenaline
Neurotransmitter binding to these receptors causes activation of adenylyl cyclase resulting in increased concentrations of cAMP and modulation of calcium ion channels within the cell. They are further classified into β1, β2, and β3 subtypes.
β1-adrenoceptors: β1-adrenoceptors...
4.4K
Sympathetic Signaling
3.4K
Sympathetic signaling, a vital part of the autonomic nervous system, plays a crucial role in mobilizing the body's resources in response to stress or emergencies. It involves the transmission of nerve impulses from sympathetic preganglionic fibers to postganglionic fibers. This results in the release of specific neurotransmitters and activation of adrenergic receptors.
Sympathetic preganglionic fibers release the neurotransmitter acetylcholine (ACh) onto the ganglionic neurons in the...
Sympathetic preganglionic fibers release the neurotransmitter acetylcholine (ACh) onto the ganglionic neurons in the...
3.4K
Adrenergic Receptors (Adrenoceptors): Classification
5.6K
Adrenergic receptors, or adrenoceptors, respond to the autonomic neurotransmitter noradrenaline and other endogenous catecholamine agonists. They are classified into two main families, α and β, based on their pharmacological response and are further subdivided depending on their location, elicited response, and affinity to specific agonists or antagonists.
α-Adrenoceptors
α-Adrenoceptors are classified into two main subtypes: α1 and α2. The α1 adrenoceptors,...
α-Adrenoceptors
α-Adrenoceptors are classified into two main subtypes: α1 and α2. The α1 adrenoceptors,...
5.6K
Activation and Inactivation of G Proteins
12.4K
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...
12.4K
Amplifying Signals via Enzymatic Cascade
19.2K
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...
19.2K
Interactions Between Signaling Pathways
7.9K
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
7.9K


