Tail engagement of arrestin at the glucagon receptor

Area of Science:

• Structural Biology
• Molecular Pharmacology
• Cellular Signaling

Background:

• Arrestins regulate G protein-coupled receptor (GPCR) signaling and internalization.
• Two proposed arrestin binding conformations (tail and core) influence distinct receptor processes.
• Limited structural data exists for arrestin's tail engagement with receptors.

Purpose of the Study:

• To determine the structural basis of β-arrestin 1 (βarr1) binding to the glucagon receptor (GCGR) in different states.
• To elucidate the role of the tail-engaged binding mode in receptor signaling and trafficking.

Main Methods:

• Determined two structures of glucagon receptor (GCGR) bound to β-arrestin 1 (βarr1) using X-ray crystallography.
• Analyzed structural features of the tail-engaged βarr1-GCGR complex.
• Conducted functional studies to assess the role of the tail conformation in receptor regulation.

Main Results:

• Revealed a novel tail-engaged binding mode of βarr1 to GCGR, distinct from previously observed interactions.
• Identified extensive interactions between GCGR's Helix VIII and βarr1's central crest.
• Demonstrated that a phosphoinositide derivative stabilizes the βarr1-GCGR complex.
• Showed the receptor core remains inactive and loosely bound to glucagon in the tail-engaged state.
• Established that the tail conformation governs βarr recruitment, GCGR endocytosis, and sustained signaling.

Conclusions:

• The tail-engaged binding of βarr1 to GCGR involves unique structural features, particularly interactions with Helix VIII.
• This binding mode is critical for regulating receptor membrane recruitment, endocytosis, and intracellular signaling.
• Provides a molecular framework for understanding how GPCRs form super-complexes for sustained signaling.