Interaction Between HAQ-STING Mutation and COPA: Protection Against COPA Syndrome

Area of Science:

• Molecular biology
• Structural biology
• Immunology

Background:

• COPA syndrome is a rare autoinflammatory disorder linked to COPA gene mutations, causing immune dysregulation.
• The HAQ variant of the stimulator of interferon genes (STING) allele acts as a protective factor.
• Understanding HAQ-STING and COPA molecular interactions is key for developing therapies.

Purpose of the Study:

• To analyze the structural interaction between COPA, STING, and the protective HAQ-STING variant.
• To investigate the potential impact of HAQ-STING on COPA protein function and stability.
• To identify potential therapeutic targets for COPA syndrome based on structural insights.

Main Methods:

• Protein complex structures were predicted using AlphaFold2 Multimer (AF2M).
• Molecular visualization and analysis of protein-protein interactions (PPIs) were performed using PyMOL.
• Molecular docking studies identified potential binding sites and interactions using AutoDock Vina Extended.

Main Results:

• HAQ-STING binding to COPA induces a 90-degree rotational shift and significant conformational changes, altering COPA's stability.
• A potential drug-binding channel was identified at the STING-COPA interface.
• Fosfomycin, a small molecule, was successfully docked into this channel, suggesting a PPI inhibition strategy.

Conclusions:

• HAQ-STING's structural modulation of COPA may underlie its protective effect in COPA syndrome.
• The identified binding channel and fosfomycin docking present a novel therapeutic target for COPA syndrome.
• Findings support exploring gene therapy, small-molecule inhibitors, and STING pathway modulation for clinical applications.