Structure of the vasopressin hormone-V2 receptor-β-arrestin1 ternary complex

Area of Science:

• Structural biology
• Molecular pharmacology
• Biochemistry

Background:

• Arrestins regulate G protein-coupled receptor (GPCR) signaling by inhibiting G protein activation and initiating downstream pathways.
• While GPCR-arrestin interactions are crucial, the structural conservation of this coupling mechanism across different GPCRs remains largely unexplored.
• Previous structural studies have provided insights into GPCR-arrestin binding, but a comprehensive understanding of variations is lacking.

Purpose of the Study:

• To determine the cryo-electron microscopy (cryo-EM) active structure of the wild-type arginine-vasopressin V2 receptor (V2R) in complex with β-arrestin1.
• To elucidate the molecular mechanisms and structural features of this specific GPCR-arrestin interaction.
• To assess the degree of structural conservation in GPCR-arrestin coupling.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was employed to obtain the high-resolution structure of the V2R-β-arrestin1 complex.
• Structural analysis focused on the interface between V2R and β-arrestin1, including receptor intracellular loops and phosphorylated carboxyl terminus sites.
• Comparative analysis with existing GPCR-arrestin structural data was performed.

Main Results:

• An active structure of the V2R-β-arrestin1 complex was determined via cryo-EM.
• β-arrestin1 adopted an atypical position compared to other known GPCR-arrestin assemblies.
• A unique V2R/β-arrestin1 interface was identified, involving all intracellular loops of the V2R and extensive interactions with phosphorylated V2R carboxyl terminus sites and the β-arrestin1 N-lobe.
• These findings align with previous data from chimeric and synthetic systems.

Conclusions:

• The V2R-β-arrestin1 complex exhibits a distinct structural arrangement, highlighting an atypical mode of interaction.
• The identified interface and interactions support existing mechanistic models while revealing novel details.
• This study underscores significant structural variability in GPCR-arrestin signaling complexes, suggesting diverse mechanisms of arrestin engagement across the GPCR superfamily.