Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP-AMP

Area of Science:

• Immunology
• Molecular Biology
• Structural Biology

Background:

• DNA pathogen infections trigger type-I interferons and inflammatory cytokines.
• Cyclic GMP-AMP synthase (cGAS) produces cGAMP, which activates stimulator of interferon genes (STING).
• STING, an endoplasmic-reticulum membrane protein, is crucial for innate immunity signaling.

Purpose of the Study:

• To elucidate the mechanism of STING activation by cGAMP.
• To determine the structural basis of STING conformational changes upon ligand binding.
• To understand STING oligomerization and its role in signal transduction.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine structures of human and chicken STING.
• Analysis of STING in inactive dimeric, cGAMP-bound dimeric, and tetrameric states.
• Structure-based mutational analyses to validate the proposed activation model.

Main Results:

• Determined cryo-EM structures of full-length human and chicken STING.
• Revealed an integrated, domain-swapped dimeric assembly of transmembrane and cytoplasmic regions.
• Showed cGAMP binding induces a 180° rotation of the ligand-binding domain, leading to tetramer formation and higher-order oligomers.

Conclusions:

• cGAMP binding to STING induces a conformational change and rotation of domains.
• This rotation triggers STING oligomerization, forming tetramers and higher-order structures essential for activation.
• The findings provide a structural model for STING-mediated innate immune signaling.