Structural basis of CD97 activation and G-protein coupling

Area of Science:

• Structural biology
• Molecular and cell biology
• Biochemistry

Background:

• CD97 (ADGRE5), an adhesion G protein-coupled receptor (aGPCR), is implicated in immune responses and cancer progression.
• The precise mechanisms governing CD97 activation and its selective coupling to specific G proteins, particularly G13, remain poorly understood.

Purpose of the Study:

• To elucidate the structural basis of CD97 activation by determining its interaction with different G proteins.
• To identify the key structural determinants responsible for CD97's selective coupling to G13 over other G proteins like Gq and Gs.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was employed to visualize the structures of human CD97 in complex with G13, Gq, and Gs.
• Comparative structural analysis was performed to identify differences in receptor-G protein interactions.

Main Results:

• The study reveals the stalk peptide recognition mode of CD97, refining the tethered-peptide activation model for aGPCRs with a revised "FXφφφ" motif and conserved aromatic residues.
• Structural comparisons highlight that a deep insertion of alpha helix 5 and closer contacts with transmembrane helices 6, 5, and 3 are critical for CD97's G13 coupling selectivity.

Conclusions:

• This structural investigation provides a foundational framework for comprehending CD97 signaling pathways.
• The findings offer crucial insights into the molecular determinants governing G13 coupling selectivity, essential for understanding CD97's biological functions in health and disease.