Petrovic Ivana, Grzesiek Stephan, Isaikina Polina
Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
Center for Life Sciences, Paul Scherrer Institut, CH-5232 Villigen, Switzerland.
Biochem Soc Trans. 2024 Dec 19;52(6):2333-2342. doi: 10.1042/BST20240170.
Arrestins are essential proteins for the regulation of G protein-coupled receptors (GPCRs). They mediate GPCR desensitization after the activated receptor has been phosphorylated by G protein receptor kinases (GRKs). In addition, GPCR-arrestin interactions may trigger signaling pathways that are distinct and independent from G proteins. The non-visual GPCRs encompass hundreds of receptors with varying phosphorylation patterns and amino acid sequences, which are regulated by only two human non-visual arrestin isoforms. This review describes recent findings on GPCR-arrestin complexes, obtained by structural techniques, biophysical, biochemical, and cellular assays. The solved structures of complete GPCR-arrestin complexes are of limited resolution ranging from 3.2 to 4.7 Å and reveal a high variability in the relative receptor-arrestin orientation. In contrast, biophysical and functional data indicate that arrestin recruitment, activation and GPCR-arrestin complex stability depend on the receptor phosphosite sequence patterns and density. At present, there is still a manifest lack of high-resolution structural and dynamical information on the interactions of native GPCRs with both GRKs and arrestins, which could provide a detailed molecular understanding of the genesis of receptor phosphorylation patterns and the specificity GPCR-arrestin interactions. Such insights seem crucial for progress in the rational design of advanced, arrestin-specific therapeutics.
抑制蛋白是调节G蛋白偶联受体（GPCR）的重要蛋白质。它们在活化的受体被G蛋白受体激酶（GRK）磷酸化后介导GPCR脱敏。此外，GPCR-抑制蛋白相互作用可能触发与G蛋白不同且独立的信号通路。非视觉GPCR包括数百种具有不同磷酸化模式和氨基酸序列的受体，它们仅由两种人类非视觉抑制蛋白亚型调节。本综述描述了通过结构技术、生物物理、生化和细胞分析获得的关于GPCR-抑制蛋白复合物的最新发现。已解析的完整GPCR-抑制蛋白复合物结构的分辨率有限，范围为3.2至4.7 Å，并且显示出受体与抑制蛋白相对取向的高度变异性。相比之下，生物物理和功能数据表明抑制蛋白的募集、激活以及GPCR-抑制蛋白复合物的稳定性取决于受体磷酸化位点的序列模式和密度。目前，关于天然GPCR与GRK和抑制蛋白相互作用的高分辨率结构和动力学信息仍然明显缺乏，而这些信息可以提供对受体磷酸化模式的产生以及GPCR-抑制蛋白相互作用特异性的详细分子理解。这些见解对于合理设计先进的、针对抑制蛋白的疗法取得进展似乎至关重要。
