Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences of Pompeu Fabra University (UPF)-Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain.
Cell Rep. 2019 Sep 24;28(13):3287-3299.e6. doi: 10.1016/j.celrep.2019.08.053.
Desensitization, signaling, and trafficking of G-protein-coupled receptors (GPCRs) are critically regulated by multifunctional adaptor proteins, β-arrestins (βarrs). The two isoforms of βarrs (βarr1 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 βarr isoforms is still lacking. By using a set of complementary approaches, including antibody-fragment-based conformational sensors, we discover structural differences between βarr1 and 2 upon their interaction with activated and phosphorylated receptors. Interestingly, domain-swapped chimeras of βarrs display robust complementation in functional assays, thereby linking the structural differences between receptor-bound βarr1 and 2 with their divergent functional outcomes. Our findings reveal important insights into the ability of βarr isoforms to drive distinct functional outcomes and underscore the importance of integrating this aspect in the current framework of biased agonism.
G 蛋白偶联受体（GPCR）的脱敏、信号转导和转运受到多功能衔接蛋白β-arrestin（βarrs）的严格调控。βarrs 的两种同工型（βarr1 和 2）具有高度的序列和结构相似性；然而，在 GPCR 信号转导和调节的背景下，它们经常介导不同的功能结果。βarr 同工型功能发散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 βarr1 和 2 在与激活和磷酸化受体相互作用时存在结构差异。有趣的是，βarrs 的结构域交换嵌合体在功能测定中表现出强大的互补性，从而将与受体结合的 βarr1 和 2 之间的结构差异与其不同的功能结果联系起来。我们的发现揭示了βarr 同工型驱动不同功能结果的能力的重要见解，并强调了在当前偏向激动剂框架中整合这一方面的重要性。
