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通过GPCR介导的β-arrestin激活以单分子精度进行解

Wesley B Asher¹, Daniel S Terry², G Glenn A Gregorio³

¹Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, USA.

|April 28, 2022

概括

在与化受体接触之前,β- 抑止素是自抑制的. 受体激活和C-tail释放对于β-arrestin激活至关重要,决定了下游的信号特异性.

科学领域:

分子和细胞生物学
生物化学
药理学

背景情况:

在G蛋白合受体 (GPCR) 信号终止和明确下游途径的启动中,β- 停滞素起着关键作用.
了解β-arrestin调节是调节GPCR介导的细胞反应的关键.

研究的目的:

调查β-arrestin的构造状态以及由化GPCRs控制其激活的机制.
阐明受体酸化模式和对β-arrestin激活的作用.

主要方法:

单分子光共振能量转移 (smFRET) 成像,以观察β-arrestin的形态动态.
使用模仿化受体尾巴的化的生物化学测试.
在生理学上评估β-arrestin激活的细胞研究.

主要成果:

贝塔逮捕素存在于一个强烈的自抑制基底状态.
与酸的接触释放了β-arrestin尾部,诱导了不同的形状.
意想不到的是,如果没有激动剂促进的受体激活,beta-arrestin与酸化受体的结合是无效的,这表明了隔离的C尾释放机制.
受体激应和C尾释放是beta-arrestin激活率和效率的关键决定因素.

结论:

β- 逮捕因子的激活是一个复杂的过程,由受体酸化和激动因子结合来调节.
酸化模式和激动性之间的协同作用决定了下游β-arrestin信号的特异性和强度.
这些发现为GPCR信号提供了新的见解,并为治疗干预提供了潜在的目标.

关键词:

与G蛋白结合的受体一个GPCR 抗生素在结构动力学化酸化条形码接收器信号传输单分子FRET 维生素B的含量

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