在G蛋白α子单元中稳定域间相互作用作为Gαi亚型信号特异性的决定因素
Tyler J Lefevre1, Wenyuan Wei2, Elizaveta Mukhaleva2
1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA; Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan, USA.
The Journal of biological chemistry
|March 24, 2024
概括
Gαi蛋白中的单个氨基酸变化解释了为什么Gαi1,但不是Gαi2,强烈激活PDZ-RhoGEF (PRG). 这一发现揭示了G蛋白信号选择性背后的机制差异.
科学领域:
- 分子生物学分子生物学
- 生物化学 生物化学
- 细胞信号传递 细胞信号传递
背景情况:
- G蛋白α子单元i (Gαi) 家庭成员Gαi1-3具有很高的同质性,但表现出不同的功能.
- PDZ-RhoGEF (PRG) 是一种新型效应因子,由Gαi1优先激活,而不是Gαi2.
研究的目的:
- 阐明Gαi1与Gαi2在激活PRG和其他标中的观察到的选择性的机制基础.
- 了解Gαi蛋白质的结构差异如何影响效应器参与.
主要方法:
- 蛋白质近距离标记屏幕用于识别Gαi相互作用的蛋白质.
- 位点导向的突变发生,以在Gαi1和Gαi2之间替换域和氨基酸.
- 分子动力学模拟和贝叶斯网络建模以分析蛋白质动力学和相互作用.
主要成果:
- 在Gαi2中取代螺旋域或单个氨基酸 (A230D) 挽救了PRG激活和目标相互作用.
- 与Gαi1相比,Gαi2在螺旋域-Ras类域接口上表现出更大的分离.
- 在Gαi2中的A230D突变稳定了相互作用,模仿Gαi1通过Switch III形态促进目标识别的能力.
结论:
- 一个单一的氨基酸差异 (Gαi1中的D229与Gαi2中的A230) 通过稳定关键相互作用来决定差异性目标参与.
- 结构变化,特别是螺旋域-Ras类域接口的结构变化,是Gαi1和Gαi2的独特生物化学性质的基础.
- 这些机制性见解解释了通过G蛋白结合受体传递Gαi1和Gαi2信号的差异性生理结果.
相关概念视频
Activation and Inactivation of G Proteins
7.1K
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...
7.1K
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
GTPases and their Regulation
8.4K
Guanine nucleotide-binding proteins (G-proteins), also known as GTPases, are a superfamily of proteins that regulate many cellular processes, such as cell signaling, vesicular transport, and the regulation of cell shape and motility. Mutation or dysfunction of these proteins can lead to disease. There are around 40,000 known G-proteins that can broadly be classified into two groups ‒ small G-proteins consisting of a single domain and large multi-domain G-proteins.
Large G-proteins,...
Large G-proteins,...
8.4K
Transducer Mechanism: G Protein–Coupled Receptors
2.0K
G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
GPCRs are also called heptahelical,...
GPCRs are also called heptahelical,...
2.0K
G-protein Coupled Receptors
118.6K
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.
118.6K
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


