University of Chicago Researchers Unveil Breakthrough Discovery on aGPCR Structure and Activation
A breakthrough study from the University of Chicago has captured detailed images of adhesion G protein-coupled receptors (aGPCRs) and identified a novel mechanism for their activation, paving the way for innovative drug development.
Understanding aGPCRs: The Untapped Potential in Pharmacology
G protein-coupled receptors (GPCRs) are integral to human physiology, with almost 35% of FDA-approved drugs targeting them. However, aGPCRs, the second-largest family of GPCRs, have yet to be effectively harnessed in therapeutic settings. These receptors play crucial roles in tissue growth, immune responses, and organ formation, while their malfunction contributes to a variety of diseases, including cancers, brain disorders, and growth issues.
Imaging Techniques Reveal aGPCR Structure and Activation Mechanisms
Researchers at the University of Chicago utilized a dual imaging approach—combining electron microscopy with Förster resonance energy transfer (FRET) imaging—to explore the full structure of a common aGPCR. Specifically, they examined Latrophilin3, which is involved in brain synapse development and is linked to conditions like attention deficit hyperactivity disorder and cancer.
Traditionally, aGPCR activation was believed to occur via ligand binding to an extracellular domain, leading to the cleavage of the GPCR Autoproteolysis INducing (GAIN) domain into two pieces, with a tethered agonist (TA) remaining attached to the transmembrane region. However, recent studies suggest that not all aGPCR functions rely on this cleavage-dependent mechanism, raising questions about alternative means of receptor activation.
New Insights into Extracellular Domain Dynamics
Dr. Demet Araç, an associate professor of biochemistry and molecular biology at the University of Chicago and senior author of the study, explains, “This opens up new opportunities for drugging adhesion GPCRs, because the extracellular region is communicating with the transmembrane region.”
Using cryo-electron microscopy (cryo-EM), the researchers stabilized the Latrophilin3 receptor’s extracellular domain with a synthetic antibody, capturing the first images of a complete aGPCR. These images revealed that the GAIN domain could assume multiple positions relative to the cell surface, indicating potential alternative activation pathways.
Exploring Conformational Coupling for Targeted Therapy
The team’s subsequent FRET imaging experiments provided critical evidence that supports the role of different GAIN domain configurations in receptor activation. By attaching fluorescent markers to both extracellular and transmembrane regions, they tracked how forces acting on these regions influenced receptor behavior.
Dr. Reza Vafabakhsh, associate professor of molecular biosciences at Northwestern University, and Dr. Kristina Cechova, a postdoctoral researcher at Northwestern, were key partners in these studies. Their findings confirm that alternate GAIN domain positions facilitate direct communication between the extracellular and transmembrane regions, suggesting new potentially reversible mechanisms for aGPCR activation.
Implications for Future Drug Development
This research opens up exciting possibilities in pharma by providing crucial structural information about aGPCRs. By understanding how these receptors function, researchers can develop more targeted drugs to treat diseases associated with aGPCR dysfunction. The study has implications not just for neurological disorders but also for cancer and growth-related pathologies.
The researchers emphasize that further research is necessary to fully elucidate the molecular mechanisms involved in aGPCR activation and to identify potential therapeutic targets. “Our findings offer a new perspective on how we might modulate these receptors,” says Dr. Araç.
Conclusion
This University of Chicago study marks a significant advance in our understanding of aGPCRs. By capturing detailed images of these complex receptors and uncovering novel activation mechanisms, researchers have taken a vital step toward developing new treatments for diseases linked to aGPCR dysfunction.
As Dr. Demet Araç concludes, “This research opens up exciting avenues for investigating how aGPCRs can be targeted for therapeutic benefit.”
To learn more about this groundbreaking research, visit: 10.1038/s41467-024-54836-4
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