G protein-coupled receptors (GPCRs) play a crucial role in the process of cellular signal transduction and are the largest family of protein targets for drugs. After activation by extracellular signaling molecules, GPCRs bind to intracellular effector proteins (G proteins, arrestins, etc.) to activate multiple downstream signaling pathways, thereby mediating and regulating various life activities in the human body. G proteins and arrestins play different roles in the signal transduction and functional regulation of GPCRs. Among them, arrestins mediate receptor desensitization and internalization. In recent years, with the deepening of structural and functional research, the mechanism of action between GPCRs and G proteins has gradually become clear. However, due to the difficulty of research, progress in the study of arrestins has been slow, and only a few complex structures of class A GPCRs and arrestins have been resolved, limiting the in-depth understanding of the mode of action of arrestins and their related physiological and pathological mechanisms.
Previous studies have found that GPCRs may interact with arrestins in two ways: one is that the core region of the receptor's transmembrane domain and the C-terminus of the receptor bind to arrestin together, known as the "core" conformation; the other is that the C-terminal region of the receptor alone interacts with arrestin, known as the "tail" conformation. These two conformations are believed to be involved in mediating different processes of receptor signal transduction and molecular transport, exerting different regulatory effects on the function of the receptor. Published GPCR and arrestin structures have predominantly featured the "core" conformation to date, leaving the workings of the "tail" conformation ambiguously elucidated.
In recent developments within the realm of G protein-coupled receptors (GPCRs), a significant leap forward in understanding signaling mechanisms has been observed. Researchers have uncovered a groundbreaking "tail" binding mode of arrestins, signifying a pivotal international breakthrough within the domain. Furthermore, the intricate dynamics underlying the interaction between Class B GPCRs and arrestins have been elucidated, revealing the intricate nuances of their functional symbiosis. This profound revelation, taking place at the atomic scale, has not only illuminated the molecular foundations of receptor internalization but has also propelled our comprehension of vesicular intracellular signal transduction. This pivotal advancement fortifies the broader understanding of the intricate signaling machinery dictating the behavior of class B receptors.
Class B GPCRs regulate various important physiological processes, and their dysfunctions are closely related to the development of diseases such as diabetes, obesity, osteoporosis, and migraines. This class of receptors can activate multiple G proteins and arrestins, mediating different physiological processes. In recent years, there has been a great deal of attention on the development of biased drugs targeting class B receptors. These drugs target specific signaling pathways, for example, by selectively activating the G protein signaling pathway or by selectively promoting the recruitment of arrestins, thus exhibiting better efficacy and lower side effects. However, the binding mode between class B GPCRs and arrestins, as well as the mechanism of biased ligand regulation, remain unclear, posing difficulties in understanding biased drug design and their pharmacological mechanisms.
To further explore the role of the "tail" conformation in the arrestin-mediated regulation of GCGR function, researchers utilized bioluminescence resonance energy transfer and other research methods to investigate dozens of amino acid mutations in the intracellular region of GCGR, exploring their effects on processes such as receptor membrane trafficking, internalization, and vesicular intracellular signal transduction. Experimental results indicate that amino acid mutations in helix VIII of GCGR have a significant impact on these physiological processes. In contrast, mutations in the core region of the receptor's transmembrane structure have little effect. These data clarify the important role of the "tail" conformation of arrestin in receptor signal transduction and molecular transport, which is of great significance for exploring the signaling and functional regulatory mechanisms of GPCRs. In the future, it may be possible to achieve selective regulation of different effector proteins and signaling pathways by designing biased drugs that specifically recognize different conformational states, thereby effectively reducing drug side effects and promoting drug development.
Reference
- Chen K.; et al. Tail engagement of arrestin at the glucagon receptor. Nature. 2023: 1-7.
.
