β-arrestin1 is an E3 ubiquitin ligase adaptor for substrate linear polyubiquitination.
β-arrestin1 is an E3 ubiquitin ligase adaptor for substrate linear polyubiquitination.
复制标题
DOI：
10.1016/j.jbc.2023.105474
复制
发表时间：
2023-12
影响因子：
4.8
通讯作者：
Marchese, Adriano
中科院分区：
文献类型：
--
作者：
Mcelrath, Chandler J.;Benzow, Sara;Zhuo, Ya;Marchese, Adriano
G蛋白偶联受体（GPCR）的信号转导和运输受多种机制的调控，包括翻译后修饰，如E3泛素连接酶的泛素化。E3连接酶已经通过与β抑制蛋白的同时结合而与激动剂刺激的GPCR的泛素化相关联。此外，β抑制蛋白已被认为有助于E3连接酶的关键效应分子的泛素化，但缺乏机制的见解。在这里，我们开发了一个体外重建系统，并表明β arr1作为一个衔接器之间的效应蛋白信号转导衔接分子1（STAM 1）和E3连接酶萎缩素相互作用蛋白4。通过质谱法，我们鉴定了STAM 1中七个被遍在蛋白化的赖氨酸残基和几种类型的遍在蛋白键合。我们提供的证据表明，βarr1促进形成线性聚泛素链在赖氨酸残基136 STAM1。该赖氨酸残基对于在GPCR活化后稳定细胞中的βarr1：STAM1相互作用是重要的。我们的研究确定了萎缩蛋白相互作用蛋白4作为唯一的第二个E3连接酶已知的共轭线性多聚泛素链和线性泛素链在GPCR信号转导和贩运的可能作用。
G protein–coupled receptor (GPCR) signaling and trafficking are regulated by multiple mechanisms, including posttranslational modifications such as ubiquitination by E3 ubiquitin ligases. E3 ligases have been linked to agonist-stimulated ubiquitination of GPCRs via simultaneous binding to βarrestins. In addition, βarrestins have been suggested to assist E3 ligases for ubiquitination of key effector molecules, yet mechanistic insight is lacking. Here, we developed an in vitro reconstituted system and show that βarrestin1 (βarr1) serves as an adaptor between the effector protein signal-transducing adaptor molecule 1 (STAM1) and the E3 ligase atrophin-interacting protein 4. Via mass spectrometry, we identified seven lysine residues within STAM1 that are ubiquitinated and several types of ubiquitin linkages. We provide evidence that βarr1 facilitates the formation of linear polyubiquitin chains at lysine residue 136 on STAM1. This lysine residue is important for stabilizing the βarr1:STAM1 interaction in cells following GPCR activation. Our study identifies atrophin-interacting protein 4 as only the second E3 ligase known to conjugate linear polyubiquitin chains and a possible role for linear ubiquitin chains in GPCR signaling and trafficking.
登录
查看更多内容
影响因子：
5.8
作者：
Raimondo, Domenico;Giorgetti, Alejandro;Tramontano, Anna
通讯作者：
Tramontano, Anna
影响因子：
16.8
作者：
Akimov, Vyacheslav;Barrio-Hernandez, Inigo;Blagoev, Blagoy
通讯作者：
Blagoev, Blagoy
影响因子：
16.6
作者：
Hansen FM;Tanzer MC;Brüning F;Bludau I;Stafford C;Schulman BA;Robles MS;Karayel O;Mann M
通讯作者：
Mann M
影响因子：
4.8
作者：
Malik, Rohit;Soh, Unice J. K.;Marchese, Adriano
通讯作者：
Marchese, Adriano
影响因子：
4.8
作者：
Bhandari, Deepali;Trejo, JoAnn;Marchese, Adriano
通讯作者：
Marchese, Adriano