Cryo-EM structure of human GPR158 receptor coupled to the RGS7-Gβ5 signaling complex

Area of Science:

• Neuroscience
• Structural Biology
• Biochemistry

Background:

• G protein-coupled receptor 158 (GPR158) is an orphan receptor highly expressed in the brain.
• GPR158 plays a role in synapse formation, function, and is implicated in depression, carcinogenesis, and cognition.
• The structural organization and signaling mechanisms of GPR158 remain largely unknown.

Purpose of the Study:

• To determine the structures of human GPR158 alone and in complex with a signaling partner.
• To elucidate the structural basis for GPR158's homodimeric organization and ligand-binding capabilities.
• To understand the structural mechanisms of GPR158 coupling to Regulator of G protein signaling (RGS) complexes.

Main Methods:

• Single-particle cryo-electron microscopy (cryo-EM) was employed to resolve the structures.
• Human GPR158 was studied both in its isolated form and when bound to an RGS signaling complex.

Main Results:

• The cryo-EM structures revealed a homodimeric organization of GPR158, stabilized by phospholipids.
• An extracellular Cache domain, an unusual feature for GPCRs, was identified as a potential ligand-binding site.
• The structural basis for GPR158 coupling to the RGS7-Gβ5 signaling complex was elucidated.

Conclusions:

• These findings provide critical structural insights into the unique biology of orphan receptors like GPR158.
• The study clarifies the formation and structural underpinnings of GPR158-GPCR-RGS signaling complexes.
• Understanding GPR158 structure opens avenues for exploring its roles in neurological disorders and cancer.