A team of researchers at the Indian Institute of Technology (IIT), Kanpur, have identified a key determinant motif in the G protein-coupled receptors (GPCRs) that facilitates its interaction with β‑arrestins. The study provides crucial insights into the complex mechanism, opening new avenues for therapeutic interventions and advancing our understanding of GPCR-mediated signalling.
GPCRs, a large family of receptors found on the surface of cells, play a vital role in transmitting signals from outside the cell to the inside. β‑arrestins are proteins that regulate the signalling process initiated by GPCRs. In the 1990s, scientists discovered that β‑arrestins not only interact with and control the activity of GPCRs but also serve as signalling adaptors. This revelation raised an intriguing question in the field: how do the two isoforms of β‑arrestins manage to identify and recognize almost 1000 GPCRs in the body? To shed light on this mystery, Jagannath Maharana, a PhD student at IIT Kanpur and the lead author of the study, expressed his motivation for pursuing this research.
A team of researchers at the Indian Institute of Technology (IIT), Kanpur, studied the molecular details of the interaction between GPCRs and β‑arrestins. In a new study, published in Molecular Cell, they have identified a specific part of GPCRs called a determinant motif, which facilitates their interaction with β‑arrestins. This finding is an important step in understanding the fundamental processes of cell signalling and molecular biology.
When a ligand binds to a GPCR, it induces a change in the receptor’s shape, leading to the recruitment of kinases, enzymes that add phosphate groups to the receptor. Phosphorylation, the addition of phosphate groups, initiates a cascade of events inside the cell, activating G proteins and further signalling by GPCRs. Simultaneously, β‑arrestins bind to the phosphorylated receptor, preventing further interaction with G proteins. This renders the receptor less responsive and internalized by the cell. Interestingly, β‑arrestins can also initiate signalling pathways independently of G proteins. The specific cellular response to GPCR activation can vary depending on factors such as the receptor type, cell type, and signalling context. Understanding how β‑arrestins bind to GPCRs is crucial due to their significant role in various biological processes and their potential as therapeutic targets.
During this study, researchers discovered a specific pattern known as the phosphorylation motif in GPCRs, which appears in certain regions of the receptor. This motif was observed to interact with another pattern in β‑arrestins, activating them and fine-tuning GPCR signalling. To gain deeper insights into this mechanism, researchers utilised cryo-electron microscopy, a technique that allowed them to determine the precise location of the phosphorylation motif. This finding contributes a significant piece to the puzzle and enhances our understanding of the complex process involved in GPCR-mediated β‑arrestin signalling.
To validate their findings, researchers made specific modifications to the identified motif by targeting the genetic sequence. They used a biosensor to observe and analyse the structural changes that occurred when β‑arrestins bound to the modified motifs. These findings reinforced the hypothesis and established the critical role of phosphorylation motifs in recruiting β‑arrestins.
This study provides important insights into the interaction and activation of GPCRs and β‑arrestins. “It marks an advancement in the understanding of GPCR signalling and has certainly opened new avenues for future research and therapeutic interventions, such as minimizing the side effects of medications,” states Maharana in the concluding statement.
Durba Sengupta, a Scientist Fellow, the National Chemical Laboratory, Pune, who is not associated with the study, commented on the findings. She said, “This is pioneering research in the field of bio-signalling, specifically targeting a previously unidentified mechanism.” Sengupta also emphasised the new possibilities for precision medicine and the significant potential for broader application in the future.
Despite the potential implications of these findings for future research in the field, several challenges remain that require attention. Kasturi Pal, Assistant Professor of Biology, Ashoka University, Haryana, expresses curiosity about the applicability of this game-changer study to other classes of GPCRs, kinases, and the diverse functions of β‑arrestins. Therefore, additional investigation and study are needed to address these challenges.