Complete Images of Adhesion GPCRs Captured

Adhesion G protein-coupled receptors (aGPCRs), a large family of cell membrane proteins involved in processes like tissue growth, immune response, and organ development, have long been challenging to study due to their size and complexity.

Now researchers from the University of Chicago have provided complete structural images of an aGPCR, shedding light on how these receptors function and offering potential strategies for drug development. The findings were published in Nature Communications.

Led by Demet Araç and Szymon Kordon, the team studied Latrophilin3, an aGPCR linked to brain synapse development, attention deficit hyperactivity disorder (ADHD), and certain cancers. Using cryo-electron microscopy (cryo-EM), they captured images of the receptor's full structure, including its extracellular region and transmembrane domain. This extracellular region extends outside the cell to bind molecules and contains the GAIN domain, which can cleave itself into two parts—a process previously thought to be essential for receptor activation.

The study revealed that the GAIN domain can adopt multiple configurations without cleaving entirely. These different positions create distinct contact points with the transmembrane region, suggesting alternative ways of signaling that do not rely on irreversible cleavage. To confirm this hypothesis, the team used Förster resonance energy transfer (FRET) imaging to track receptor movements under adhesion forces. They found that different conformations corresponded to varied signaling activities within the cell.

“This opens up new opportunities for drugging adhesion GPCRs,” Araç explained. By engineering antibodies to stabilize or manipulate specific receptor conformations, researchers could develop precise drugs targeting aGPCRs without affecting other receptors. With 33 aGPCRs identified in humans, this approach holds promise for addressing diseases linked to these complex proteins.