Conformational Sensors and Domain Swapping Reveal Structural and Functional Differences between β-Arrestin Isoforms
Conformational Sensors and Domain Swapping Reveal Structural and Functional Differences between β-Arrestin Isoforms
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DOI：
10.1016/j.celrep.2019.08.053
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发表时间：
2019-09-24
期刊：
影响因子：
8.8
通讯作者：
Shukla, Arun K.
中科院分区：
文献类型：
--
作者：
Ghosh, Eshan;Dwivedi, Hemlata;Shukla, Arun K.
g蛋白偶联受体（gpcr）的脱敏、信号传导和转运受到多功能衔接蛋白、β -阻滞蛋白（β - arrs）的关键调控。β arrs的两个同工型（β arr1和β ar2）具有高度的序列和结构相似性；然而，在GPCR信号和调控的背景下，它们经常介导不同的功能结果。这种β - arr同工异构体功能分化的机制基础仍然缺乏。通过使用一组互补的方法，包括基于抗体片段的构象传感器，我们发现β arr1和β arr1与活化和磷酸化受体相互作用时的结构差异。有趣的是，β - arrs的结构域交换嵌合体在功能分析中显示出强大的互补，从而将受体结合β - arr1和2之间的结构差异与其不同的功能结果联系起来。我们的研究结果揭示了β - arr亚型驱动不同功能结果的能力的重要见解，并强调了将这方面整合到当前偏倚激动作用框架中的重要性。
Desensitization, signaling, and trafficking of G-protein-coupled receptors (GPCRs) are critically regulated by multifunctional adaptor proteins, beta-arrestins (beta arrs). The two isoforms of beta arrs (beta arr1 and 2) share a high degree of sequence and structural similarity; still, however, they often mediate distinct functional outcomes in the context of GPCR signaling and regulation. A mechanistic basis for such a functional divergence of beta arr isoforms is still lacking. By using a set of complementary approaches, including antibody-fragment-based conformational sensors, we discover structural differences between beta arr1 and 2 upon their interaction with activated and phosphorylated receptors. Interestingly, domain-swapped chimeras of beta arrs display robust complementation in functional assays, thereby linking the structural differences between receptor-bound beta arr1 and 2 with their divergent functional outcomes. Our findings reveal important insights into the ability of beta arr isoforms to drive distinct functional outcomes and underscore the importance of integrating this aspect in the current framework of biased agonism.